A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.

BACKGROUND: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks. METHODS: Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients. RESULTS: Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment. CONCLUSIONS: AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.

Combining epidemiology and economics to assess control of a viral endemic animal disease: Porcine Reproductive and Respiratory Syndrome (PRRS).

Porcine reproductive and respiratory syndrome (PRRS) is an extremely contagious disease that causes great damage to the U.S. pork industry. PRRS is not subject to official control in the U.S., but most producers adopt control strategies, including vaccination. However, the PRRS virus mutates frequently, facilitating its ability to infect even vaccinated animals. In this paper we analyze how increased vaccination on sow farms reduces PRRS losses and when vaccination is profitable. We develop a SIR model to simulate the spread of an outbreak between and within swine farms located in a region of Minnesota. Then, we estimate economic losses due to PRRS and calculate the benefits of vaccination. We find that increased vaccination of sow farms increases the private profitability of vaccination, and also transmits positive externalities to farms that do not vaccinate. Although vaccination reduces industry losses, a low to moderate vaccine efficacy implies that large PRRS losses remain, even on vaccinated farms. Our approach provides useful insight into the dynamics of an endemic animal disease and the benefits of different vaccination regimens.

Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases.

N-Methylated amino acids (N-MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, de novo discovery from ribosome display is limited by poor incorporation of N-methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the N-methyl-aminoacyl-tRNA. By reconfiguring the tRNA's T-stem region to compensate and tune the EF-Tu affinity, we conducted Random nonstandard Peptides Integrated Discovery (RaPID) display of a macrocyclic peptide (MCP) library containing six different N-MeAAs. We have here devised a "pool-and-split" enrichment strategy using the RaPID display and identified N-methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% N-methylation with up to three consecutively incorporated N-MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by N-methylation, were identified. Co-crystal structures reveal an architecturally related Ce-2 Ipglycermide active-site metal-ion-coordinating Cys lariat MCP, functionally dependent on two cis N-MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent Staphylococcus aureus iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the N-MeAA MCP library.

Production Losses From an Endemic Animal Disease: Porcine Reproductive and Respiratory Syndrome (PRRS) in Selected Midwest US Sow Farms.

Porcine reproductive and respiratory syndrome (PRRS) is an endemic disease causing important economic losses to the US swine industry. The complex epidemiology of the disease, along with the diverse clinical outputs observed in different types of infected farms, have hampered efforts to quantify PRRS' impact on production over time. We measured the impact of PRRS on the production of weaned pigs using a log-linear fixed effects model to evaluate longitudinal data collected from 16 sow farms belonging to a specific firm. We measured seven additional indicators of farm performance to gain insight into disease dynamics. We used pre-outbreak longitudinal data to establish a baseline that was then used to estimate the decrease in production. A significant rise of abortions in the week before the outbreak was reported was the strongest signal of PRRSV activity. In addition, production declined slightly one week before the outbreak and then fell markedly until weeks 5 and 6 post-outbreak. Recovery was not monotonic, cycling gently around a rising trend. At the end of the study period (35 weeks post-outbreak), neither the production of weaned pigs nor any of the performance indicators had fully recovered to baseline levels. This result suggests PRSS outbreaks may last longer than has been found in most other studies. We assessed PRRS' effect on farm efficiency as measured by changes in sow production of weaned pigs per year. We translated production losses into revenue losses assuming an average market price of $45.2/weaned pig. We estimate that the average PRSS outbreak reduced production by approximately 7.4%, relative to annual output in the absence of an outbreak. PRRS reduced production by 1.92 weaned pigs per sow when adjusted to an annual basis. This decrease is substantially larger than the 1.44 decrease of weaned pigs per sow/year reported elsewhere.

Using Machine Learning to Predict Swine Movements within a Regional Program to Improve Control of Infectious Diseases in the US.

Between-farm animal movement is one of the most important factors influencing the spread of infectious diseases in food animals, including in the US swine industry. Understanding the structural network of contacts in a food animal industry is prerequisite to planning for efficient production strategies and for effective disease control measures. Unfortunately, data regarding between-farm animal movements in the US are not systematically collected and thus, such information is often unavailable. In this paper, we develop a procedure to replicate the structure of a network, making use of partial data available, and subsequently use the model developed to predict animal movements among sites in 34 Minnesota counties. First, we summarized two networks of swine producing facilities in Minnesota, then we used a machine learning technique referred to as random forest, an ensemble of independent classification trees, to estimate the probability of pig movements between farms and/or markets sites located in two counties in Minnesota. The model was calibrated and tested by comparing predicted data and observed data in those two counties for which data were available. Finally, the model was used to predict animal movements in sites located across 34 Minnesota counties. Variables that were important in predicting pig movements included between-site distance, ownership, and production type of the sending and receiving farms and/or markets. Using a weighted-kernel approach to describe spatial variation in the centrality measures of the predicted network, we showed that the south-central region of the study area exhibited high aggregation of predicted pig movements. Our results show an overlap with the distribution of outbreaks of porcine reproductive and respiratory syndrome, which is believed to be transmitted, at least in part, though animal movements. While the correspondence of movements and disease is not a causal test, it suggests that the predicted network may approximate actual movements. Accordingly, the predictions provided here might help to design and implement control strategies in the region. Additionally, the methodology here may be used to estimate contact networks for other livestock systems when only incomplete information regarding animal movements is available.

Measuring Progress on the Control of Porcine Reproductive and Respiratory Syndrome (PRRS) at a Regional Level: The Minnesota N212 Regional Control Project (Rcp) as a Working Example.

Due to the highly transmissible nature of porcine reproductive and respiratory syndrome (PRRS), implementation of regional programs to control the disease may be critical. Because PRRS is not reported in the US, numerous voluntary regional control projects (RCPs) have been established. However, the effect of RCPs on PRRS control has not been assessed yet. This study aims to quantify the extent to which RCPs contribute to PRRS control by proposing a methodological framework to evaluate the progress of RCPs. Information collected between July 2012 and June 2015 from the Minnesota Voluntary Regional PRRS Elimination Project (RCP-N212) was used. Demography of premises (e.g. composition of farms with sows = SS and without sows = NSS) was assessed by a repeated analysis of variance. By using general linear mixed-effects models, active participation of farms enrolled in the RCP-N212, defined as the decision to share (or not to share) PRRS status, was evaluated and used as a predictor, along with other variables, to assess the PRRS trend over time. Additionally, spatial and temporal patterns of farmers' participation and the disease dynamics were investigated. The number of farms enrolled in RCP-N212 and its geographical coverage increased, but the proportion of SS and NSS did not vary significantly over time. A significant increasing (p<0.001) trend in farmers' decision to share PRRS status was observed, but with NSS producers less willing to report and a large variability between counties. The incidence of PRRS significantly (p<0.001) decreased, showing a negative correlation between degree of participation and occurrence of PRRS (p<0.001) and a positive correlation with farm density at the county level (p = 0.02). Despite a noted decrease in PRRS, significant spatio-temporal patterns of incidence of the disease over 3-weeks and 3-kms during the entire study period were identified. This study established a systematic approach to quantify the effect of RCPs on PRRS control. Despite an increase in number of farms enrolled in the RCP-N212, active participation is not ensured. By evaluating the effect of participation on the occurrence of PRRS, the value of sharing information among producers may be demonstrated, in turn justifying the existence of RCPs.

Beef muscle troponin: evidence for multiple forms of troponin-T.

A method is described for the purification of troponin from beef skeletal muscle. The resultant preparation differs from the troponin of rabbit skeletal muscle in that it contains at least two forms of the tropomyosin-binding component, Troponin-T: these are designated as the 37 000 and 40 000 dalton forms of Troponin-T on the basis of sodium dodecyl sulphate gel electrophoresis. Either of these Troponin-T forms may be used to reconstitute troponin by mixing with the appropriate amounts of the calcium-binding (Troponin-C) and and actomyosin ATPase-inhibitory (Troponin-I) components. These reconstituted troponins are shown to interact with tropomyosin and also to confer full calcium sensitivity on actomyosin ATPase. Despite the existence of proteolysis in troponin preparations, the experimental evidence indicates that the smaller form of Troponin-T is not derived from the 40 000 dalton species by limited degradation. Although both species of Troponin-T have been found routinely in troponin from beef skeletal muscle, only the larger form is detected in troponin preparations from beef cardiac muscle. Further studies are required in order to clarify the functional significance and differential distribution of these multiple forms of Troponin-T.

Properties of polyproline II, a secondary structure element implicated in protein-protein interactions.

The polyproline II (PPII) conformation of protein backbone is an important secondary structure type. It is unusual in that, due to steric constraints, its main-chain hydrogen-bond donors and acceptors cannot easily be satisfied. It is unable to make local hydrogen bonds, in a manner similar to that of alpha-helices, and it cannot easily satisfy the hydrogen-bonding potential of neighboring residues in polyproline conformation in a manner analogous to beta-strands. Here we describe an analysis of polyproline conformations using the HOMSTRAD database of structurally aligned proteins. This allows us not only to determine amino acid propensities from a much larger database than previously but also to investigate conservation of amino acids in polyproline conformations, and the conservation of the conformation itself. Although proline is common in polyproline helices, helices without proline represent 46% of the total. No other amino acid appears to be greatly preferred; glycine and aromatic amino acids have low propensities for PPII. Accordingly, the hydrogen-bonding potential of PPII main-chain is mainly satisfied by water molecules and by other parts of the main-chain. Side-chain to main-chain interactions are mostly nonlocal. Interestingly, the increased number of nonsatisfied H-bond donors and acceptors (as compared with alpha-helices and beta-strands) makes PPII conformers well suited to take part in protein-protein interactions.

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma.

PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. CONCLUSION: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.

Irinotecan therapy in adults with recurrent or progressive malignant glioma.

PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.

Cooperativity in Bacillus stearothermophilus pyruvate kinase.

The enzyme pyruvate kinase (PK) from the moderate thermophile Bacillus stearothermophilus has been used as a model system with which to investigate the homotropic and heterotropic cooperative interactions of the enzyme. Cooperative ligand binding by the wild-type enzyme was measured using pre-steady-state and steady-state fluorescence spectroscopy, and steady-state kinetics. The results suggest that the cooperative structural changes induced by the substrate phosphoenolpyruvate (PEP) are distinct from those induced by the allosteric activator ribose- 5-phosphate (R5P). Furthermore the structural transition induced by the binding of saturating amounts of both PEP and R5P is itself distinct. This conclusion was further substantiated by the production of five mutant proteins in which the R5P- and PEP-induced homotropic cooperative transitions were separated. These results suggest that the cooperativity exhibited by pyruvate kinase from B. stearothermophilus does not conform to a simple two-state model. A putative four-state model is proposed.

Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation.

Small-probe contact dot surface analysis, with all explicit hydrogen atoms added and their van der Waals contacts included, was used to choose between the two possible orientations for each of 1554 asparagine (Asn) and glutamine (Gln) side-chain amide groups in a dataset of 100 unrelated, high-quality protein crystal structures at 0.9 to 1.7 A resolution. For the movable-H groups, each connected, closed set of local H-bonds was optimized for both H-bonds and van der Waals overlaps. In addition to the Asn/Gln "flips", this process included rotation of OH, SH, NH3+, and methionine methyl H atoms, flip and protonation state of histidine rings, interaction with bound ligands, and a simple model of water interactions. However, except for switching N and O identity for amide flips (or N and C identity for His flips), no non-H atoms were shifted. Even in these very high-quality structures, about 20 % of the Asn/Gln side-chains required a 180 degrees flip to optimize H-bonding and/or to avoid NH2 clashes with neighboring atoms (incorporating a conservative score penalty which, for marginal cases, favors the assignment in the original coordinate file). The programs Reduce, Probe, and Mage provide not only a suggested amide orientation, but also a numerical score comparison, a categorization of the marginal cases, and a direct visualization of all relevant interactions in both orientations. Visual examination allowed confirmation of the raw score assignment for about 40 % of those Asn/Gln flips placed within the "marginal" penalty range by the automated algorithm, while uncovering only a small number of cases whose automated assignment was incorrect because of special circumstances not yet handled by the algorithm. It seems that the H-bond and the atomic-clash criteria independently look at the same structural realities: when both criteria gave a clear answer they agreed every time. But consideration of van der Waals clashes settled many additional cases for which H-bonding was either absent or approximately equivalent for the two main alternatives. With this extra information, 86 % of all side-chain amide groups could be oriented quite unambiguously. In the absence of further experimental data, it would probably be inappropriate to assign many more than this. Some of the remaining 14 % are ambiguous because of coordinate error or inadequacy of the theoretical model, but the great majority of ambiguous cases probably occur as a dynamic mix of both flip states in the actual protein molecule. The software and the 100 coordinate files with all H atoms added and optimized and with amide flips corrected are publicly available.

Visualizing and quantifying molecular goodness-of-fit: small-probe contact dots with explicit hydrogen atoms.

The technique of small-probe contact dot surfaces is described as a method for calculating and displaying the detailed atomic contacts inside or between molecules. It allows one both to measure and to visualize directly the goodness-of-fit of packing interactions. It requires both highly accurate structures and also the explicit inclusion of all hydrogen atoms and their van der Waals interactions. A reference dataset of 100 protein structures was chosen on the basis of resolution (1.7 A or better), crystallographic R-value, non-homology, and the absence of any unusual problems. Hydrogen atoms were added in standard geometry and, where needed, with rotational optimization of OH, SH, and NH+3 positions. Side-chain amide orientations were corrected where required by NH van der Waals clashes, as described in the accompanying paper. It was determined that, in general, methyl groups pack well in the default staggered conformation, except for the terminal methyl groups of methionine residues, which required rotational optimization. The distribution of serious clashes (i.e. non-H-bond overlap of >/=0.4 A) was studied as a function of resolution, alternate conformations, and temperature factor (B), leading to the decision that packing and other structural features would not be analyzed for residues in 'b' alternate conformations or with B-factors of 40 or above. At the level of the fine details analyzed here, structural accuracy improves quite significantly over the range from 1.7 to 1.0 A resolution. These high-resolution structures show impressively well-fitted packing interactions, with some regions thoroughly interdigitated and other regions somewhat sparser. Lower-resolution structures or model structures could undoubtedly be improved in accuracy by the incorporation of this additional information: for example, nucleic acid structures in non-canonical conformations are often very accurate for the bases and much less reliable for the backbone, whose conformation could be specified better by including explicit H atom geometry and contacts. The contact dots are an extremely sensitive method of finding problem areas, and often they can suggest how to make improvements. They can also provide explanations for structural features that have been described only as empirical regularities, which is illustrated by showing that the commonest rotamer of methionine (a left-handed spiral, with all chi values near -60 degrees) is preferred because it provides up to five good H atom van der Waals contacts. This methodology is thus applicable in two different ways: (1) for finding and correcting errors in structure models (either experimental or theoretical); and (2) for analyzing interaction patterns in the molecules themselves.

Manipulating enteric methane emissions and animal performance of late-lactation dairy cows through concentrate supplementation at pasture.

The objective of this study was to determine the potential of increased fiber-based concentrates to reduce methane (CH(4)) production in relation to milk yield from late-lactation dairy cows. The effect of 2 levels of concentrate supplementation (0.87 vs. 5.24 kg on a dry matter basis) on herbage voluntary intake, total dry matter intake, milk yield, milk composition, and CH(4) production were determined by way of a randomized block designed grazing trial using lactating Holstein-Friesian cows (231 +/- 44 d in milk) grazing a mixed-grass sward with a regrowth aged 36 d. Increased concentrate supplementation resulted in a significant increase in total dry matter intake, milk yield, fat-corrected milk (FCM) yield, and daily CH(4) production. However, herbage intake and milk composition were unaffected. Although daily CH(4) production increased with fibrous concentrate use the increase was not as great as that observed for milk yield. The decline in CH(4) production per kilogram of milk was nonsignificant; however, when relating CH(4) production to FCM(FCM at 35 g of fat/kg of milk), a declining trend was identified within increasing concentrate supplementation (19.26 and 16.02 g of CH(4)/kg of FCM). These results suggest that increased fibrous concentrate use at pasture, even at modest levels, could reduce enteric CH(4) production per kilogram of animal product. However, the effectiveness of such a strategy is dependent on the maintenance of production quotas and a subsequent decline in the number of livestock needed to fulfill the specified production level.

Exploring steric constraints on protein mutations using MAGE/PROBE.

When planning a mutation to test some hypothesis, one crucial question is whether the new side chain is compatible with the existing structure; only if it is compatible can the interpretation of mutational results be straightforward. This paper presents a simple way of using the sensitive geometry of all-atom contacts (including hydrogens) to answer that question. The interactive MAGE/PROBE system lets the biologist explore conformational space for the mutant side chain, with an interactively updated kinemage display of its all-atom contacts to the original structure. The Autobondrot function in PROBE systematically explores that same conformational space, outputting contact scores at each point, which are then contoured and displayed. These procedures are applied here in two types of test cases, with known mutant structures. In ricin A chain, the ability of a neighboring glutamate to rescue activity of an active-site mutant is modeled successfully. In T4 lysozyme, six mutations to Leu are analyzed within the wild-type background structure, and their Autobondrot score maps correctly predict whether or not their surroundings must shift significantly in the actual mutant structures; interactive examination of contacts for the conformations involved explains which clashes are relieved by the motions. These programs are easy to use, are available free for UNIX or Microsoft Windows operating systems, and should be of significant help in choosing good mutation experiments or in understanding puzzling results.

Pharmacy-based needle exchange (PBNX) schemes in south east England: a survey of service providers.

AIMS: To describe the activities of service providers with regard to (i) the business operation and policies defining pharmacy-based needle exchange (PBNX) in South East England; (ii) the day-to-day work of PBNX outlets from the provider perspective; and (iii) problems encountered by PBNX providers. DESIGN: (i) Postal self-completion questionnaire to all participating PBNX community pharmacies in South East England; and (ii) postal self-completion questionnaire to needle exchange coordinators. SETTING: Community pharmacy needle exchanges. PARTICIPANTS: Pharmacists in charge of needle exchange; and needle exchange coordinators. FINDINGS: Data were collected (i) from 381/440 (86.7%) participating community pharmacists, and (ii) 32/36 (88.9%) of coordinators. The study found that PBNX was reaching injecting drug users (many of whom used PBNX regularly), and providing a wide range of injecting equipment. Although pharmacists reported that problems such as shoplifting occurred relatively frequently, more serious problems such as violence were relatively rare. However, PBNX pharmacists reported needing further training for themselves and their staff. Suggested improvements included better advertising of services and improving returns rates for used injecting equipment. CONCLUSION: Needle exchange can reasonably be provided by non-specialist health care professionals such as community pharmacists. However, attention should to be paid to the educational needs of service providers who also require adequate support.

A flow calorimetric method of determining electron beam energy.

The construction of an adiabatic flow calorimeter using water as the working substance is described. It is shown that at high dose rates the heat defect due to chemical reactions in water is small (of the order of 0-3%) and that under high dose rate conditions flow calorimetry can be used as a method of measuring the energy of high intensity electron beams. Measurements made with a 15 MeV linear accelerator are reported and compared with magnetic measurements.

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

Results of a survey of nurse anesthesia education programs: diversity, growth and regionalization.

This survey was conducted in June of 1990. Questionnaires were sent to and data obtained from all civilian and military nurse anesthesia education programs. Programs were asked to provide the following information: type of conducting institution; the party responsible for the administrative costs of the program; name and location of the program's academic affiliation; the name, location, type and purpose of all clinical affiliations/sites; and distance from the conducting institution to the academic affiliation and to each clinical site. The conducting entities for civilian programs were as follows: hospital or medical center, 43 programs; academic institution, 15 programs; joint arrangement between a hospital and an academic institution, 10 programs; freestanding, 4 programs; other, 7 programs. For purposes of this survey, each branch of the military was considered to have a single program with multiple clinical sites. Two military programs identified their conducting entity as a joint arrangement between the respective branch of the military and an academic institution. The third program identified itself as freestanding with an academic affiliation. In all but seven programs, the administrative costs of the program are the responsibility of the conducting institution. The majority of programs (74%) have an academic affiliation and 68% of programs offer a graduate degree. Eighty percent of programs with an academic affiliation are located within 50 miles of the academic site. The greatest distance between a program and its academic affiliation is 350 miles. Programs reported having from 1-13 clinical sites (mean = 3.6 sites/program). Military programs, freestanding programs and programs conducted by an academic institution have the highest mean number of sites per program.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-effective anesthesia: desflurane versus propofol in outpatient surgery.

This study compared the costs of desflurane and propofol as maintenance anesthetic agents in outpatient surgery. Recovery time and related drug expenses were included in the cost comparison. Fifty-three ASA physical status I and II patients were randomly assigned to receive a maintenance anesthetic of either desflurane with 50% nitrous oxide or propofol with 50% nitrous oxide. All patients received a propofol induction and were administered narcotics, sedatives, muscle relaxants, reversal agents, and antiemetics as determined necessary by the anesthesia provider. The mean propofol cost was $31.88 +/- 14.44, whereas, the mean desflurane cost was $12.99 +/- 7.61 (P < .05). The mean cost of all medications, anesthetics, and ancillary agents included was $57.97 +/- 20.22 for the propofol group and $34.86 +/- 14.13 for the desflurane group (P < .05). Of the desflurane patients, 41% experienced nausea compared to 12% of the propofol patients (P < .05). There was no significant difference between the recovery times of the two groups. Desflurane was more cost-effective than propofol. Although desflurane patients experienced more nausea, this did not affect their discharge time.