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Six to nine populations of the diamondback moth, Plutella xylostella (L.), were collected annually from fields of crucifer vegetables in the United States and Mexico from 2001 to 2004 for baseline susceptibility tests and resistance monitoring to spinosad, indoxacarb, and emamectin benzoate. A discriminating concentration for resistance monitoring to indoxacarb and emamectin benzoate was determined based on baseline data in 2001 and was used in the diagnostic assay for each population in 2002-2004 together with a discriminating concentration for spinosad determined previously. Most populations were susceptible to all three insecticides, but a population from Hawaii in 2003 showed high levels of resistance to indoxacarb. Instances of resistance to spinosad occurred in Hawaii (2000), Georgia (2001), and California (2002) as a consequence of a few years of extensive applications in each region. The collaborative monitoring program between university and industry scientists we discuss in this article has provided useful information to both parties as well as growers who use the products. These studies provide a baseline for developing a more effective resistance management program for diamondback moth.

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Fourteen populations of the diamondback moth, Plutella xylostella (L.), were collected from fields of crucifer vegetables in the United States, Mexico, and Thailand in 1999 and 2000 for susceptibility tests with spinosad. Most populations were susceptible to spinosad and similar to earlier baseline values, but populations from Thailand and Hawaii showed high levels of tolerance. A statewide survey in Hawaii in 2000 and 2001 indicated resistance problems on several islands. One colony collected in October 2000 from Pearl City, HI, was subjected to further selection pressure, using spinosad in the laboratory, and then was used as the resistant strain (Pearl-Sel) for other tests. Spray tests using the recommended field rates of spinosad on potted broccoli plants in the greenhouse confirmed that field control failures due to resistance were possible in the areas of these collections. Analysis of probit lines from F1 reciprocal crosses between the Pearl-Sel and S strain indicated that resistance to spinosad was inherited autosomally and was incompletely recessive. A direct test of monogenic inheritance based on the F1 x Pearl-Sel backcrosses suggested that resistance to spinosad was probably controlled by one locus. The synergists S,S,S-tributyl phosphorotrithioate and piperonyl butoxide did not enhance the toxicity of spinosad to the resistant colony, indicating metabolic mediated detoxification was probably not responsible for the spinosad resistance. Two field colonies in Hawaii that were resistant to spinosad were not cross-resistant to emamectin benzoate or indoxacarb. Resistance developed in Hawaii due to the continuous cultivation of crucifers in which as many as 50 applications of spinosad per year may have been made to a common population of P. xylostella in sequential plantings, although each grower might have used the labeled restrictions for resistance management. Resistance management strategies will need to address such cropping and pest management practices.

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Argininosuccinate lyase (ASL) catalyzes the reversible breakdown of argininosuccinate to arginine and fumarate, a reaction involved in the biosynthesis of arginine in all species and in the production of urea in ureotelic species. In humans, mutations in the enzyme result in the autosomal recessive disorder argininosuccinic aciduria. Intragenic complementation has been demonstrated to occur at the ASL locus, with two distinct classes of ASL-deficient strains having been identified, the frequent and high-activity complementers. The frequent complementers participate in the majority of the complementation events observed and were found to be either homozygous or heterozygous for a glutamine to arginine mutation at residue 286. The three-dimensional structure of the frequently complementing allele Q286R has been determined at 2.65 A resolution. This is the first high-resolution structure of human ASL. Comparison of this structure with the structures of wild-type and mutant duck delta1 and delta2 crystallins suggests that the Q286R mutation may sterically and/or electrostatically hinder a conformational change in the 280's loop (residues 270-290) and domain 3 that is thought to be necessary for catalysis to occur. The comparison also suggests that residues other than R33, F333, and D337 play a role in maintaining the structural integrity of domain 1 and reinforces the suggestion that residues 74-89 require a particular conformation for catalysis. The electron density has enabled the structure of residues 6-18 to be modeled for the first time. Residues 7-9 and 15-18 are in type IV beta-turns and are connected by a loop. The conformation observed is stabilized, in part, by a salt bridge between the side chains of R12 and D18. Although the disease causing mutation R12Q would disrupt this salt bridge, it is unclear why this mutation has such a significant effect on the catalytic activity as residues 1-18 are disordered in all other delta-crystallin structures determined to date.

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Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate. Deficiencies in the enzyme result in the autosomal, recessive disorder argininosuccinic aciduria. Considerable clinical and genetic heterogeneity is associated with this disorder, which is thought to be a consequence of the extensive intragenic complementation identified in patient strains. Our ability to predict genotype-phenotype relationships is hampered by the current lack of understanding of the mechanisms by which complementation can occur. The 3-dimensional structure of wild-type ASL has enabled us to propose that the complementation between two ASL active site mutant subunits, Q286R and D87G, occurs through a regeneration of functional active sites in the heteromutant protein. We have reconstructed this complementation event, both in vivo and in vitro, using recombinant proteins and have confirmed this hypothesis. The complementation events between Q286R and two nonactive site mutants, M360T and A398D, have also been characterized. The M360T and A398D substitutions have adverse effects on the thermodynamic stability of the protein. Complementation between either the M360T or the A398D mutant and the stable Q286R mutant occurs through the formation of a more stable heteromeric protein with partial recovery of catalytic activity. The detection and characterization of a novel complementation event between the A398D and D87G mutants has shown how complementation in patients with argininosuccinic aciduria may correlate with the clinical phenotype.

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OBJECTIVES: To determine the medical conditions for which selected analgesics are most frequently prescribed in nursing facilities (NFs), describe the use of pharmacologic and nonpharmacologic pain therapies, and determine the frequency and quality of pain assessment in NF residents. DESIGN: A multicenter, 3-month retrospective drug use evaluation conducted by consultant pharmacists. SETTING: Eighty-nine NFs having no more than 25% of their patient census representing special populations (e.g., head trauma). PARTICIPANTS: A total of 2065 adult NF residents who received at least one selected analgesic. MEASUREMENTS: Primary indication for analgesics, pain type, method of pain assessment, nonpharmacologic therapies for pain, prescribed analgesics and regimens, and comorbid conditions were recorded. RESULTS: A total of 54.3% of residents had one indication for analgesic therapy, 31.0% had two indications, and 14.7% had three or more indications. Arthritis was the most prevalent indication for analgesics (41.7% of residents), followed by bone fracture (12.4%) and other musculoskeletal conditions (9.7%). More residents (76.8%) were reported to have chronic pain than acute pain (19.9%), and 3.0% had both chronic and acute pain. Pain type was unknown for 0.2% of residents. Observational pain assessments were used more frequently (for 55.9% of residents) than objective methods (16.6%), and pain was not assessed in 40.6% of residents. Most residents (69.4%) received no nonpharmacologic treatment for pain. Of the 2542 opioid and nonsteroidal anti-inflammatory drug (NSAID) prescriptions, 67.6% were for opioids, 24.8% were for NSAIDs, and 7.6% were for tramadol. Propoxyphene-containing drugs were the most frequently prescribed opioid group, and propoxyphene with acetaminophen was the most frequently prescribed analgesic (35.6% of all analgesics). Most analgesics (63.2%) were prescribed on an as-needed (prn) basis. CONCLUSIONS: The findings show a lack of adequate pain assessments, little use of nonpharmacologic interventions, and inappropriate use of analgesic medication. The small percentage of residents with chronic pain assessed objectively suggests the difficulty of monitoring pain progression in NFs. The prescribing of analgesic for most residents (with propoxyphene used most often, long-acting opioids used infrequently, and frequent prn use) was inconsistent with recommended pain therapy in older people and attests to the urgent need to educate NF practitioners on the appropriate use of analgesics.

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OBJECTIVES: To describe the prescribing and use of antiepileptic drug (AED) therapy in nursing facility residents. DESIGN: A retrospective, multicenter drug use evaluation. SETTING: A total of 85 nursing facilities (average size, 119 beds) in five states. PARTICIPANTS: 1132 residents of the total 10,168 residents screened were prescribed at least one AED. MEASURES: Demographic information, primary indication for AED, comorbid conditions, prescribing physician's specialty, concomitant medications, and AED dosage regimen information were collected. Laboratory tests obtained in the most recent 6 months and seizure occurrence and seizure-related diagnostic assessments made in the most recent 3 months were also recorded. RESULTS: Of 1132 residents receiving AED therapy, 892 (78.8%) were prescribed AED therapy for a seizure-related diagnosis although 86% of seizure types were unspecified. Another 215 residents (19.0%) were prescribed AEDs for nonseizure diagnoses, and 25 (2.2%) had no indication for AED therapy. AEDs most frequently prescribed were phenytoin (56.8%), carbamazepine (23.0%), phenobarbital (15.6%), and valproic acid (13.1%). For residents with a seizure diagnosis, the most frequently prescribed monotherapy agents were phenytoin (52.0%), carbamazepine (12.2%), and phenobarbitol (7.1%). Almost 25% of residents with a seizure diagnosis took a combination of AEDs; more than 50% of all combinations included phenobarbital. About 9% of residents with a seizure diagnosis had one or more documented seizures during a 3-month review period. CONCLUSION: Among the substantial percentage of residents treated with AEDs, the lack of diagnosis of seizure type has serious implications for the choice of AED therapy. Opportunities exist for prescribing physicians, consultant pharmacists, and nursing staff to improve the medical management of nursing facility residents with seizures and of others receiving AEDs.

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Race and level of physical activity may be important factors affecting cardiovascular responsiveness to acute sodium intake. We examined the effects of a 4-day sodium loading procedure on heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure, 24-hour electrolyte excretion, and extracellular fluid volume (ECF) in African-American (n = 16) and Caucasian (n = 16) adult males. All subjects were normotensive with either moderately high (> or = 3 day/wk; > or = 20 min/day) or low (< or = 3 day/wk; < or = 20 min/day) physical activity levels. Subjects ingested either placebo or NaCl (0.2 g/kg/day) during two 4-day periods. Sodium loading increased SBP and decreased HR in all high physical activity subjects but not in low physical activity subjects (p < 0.05). Na+ excretion did not differ among groups, although urine volume and K+ excretion were lower, and Na+/K+ excretion ratio was higher in African-American compared to Caucasian subjects (p < 0.05). ECF, as measured by NaBr dilution, was greater in high physical activity subjects compared to low physical activity subjects (p < 0.05). These data suggest that high physical activity levels do not attenuate but rather exaggerate SBP response to a sodium load.

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OBJECTIVE: To determine whether peripheral hemodynamic differences exist in young adult normotensive African Americans and white Americans with a positive and negative parental history of hypertension. METHODS: The participants were healthy men of whom 13 were African Americans and nine white Americans with a positive parental history and 19 were African Americans and 13 white Americans with a negative parental history. Lower leg blood flows were obtained at rest and during reactive hyperemia. Lower leg minimum vascular resistance (Rmin) was computed from reactive hyperemic blood flow measured by venous occlusion plethysmography, and mean arterial blood pressure was determined by auscultation of the brachial artery. RESULTS: Resting blood flow and mean arterial pressure were similar in all groups. A significant race x parental history interaction effect was observed for lower leg Rmin. In the white men the lower leg Rmin was significantly greater in the positive than the negative parental group (P < 0.05). Lower leg Rmin was significantly greater in African Americans than in white men without a parental histoy (P < 0.05). Mean arterial blood pressure and heart rate were similar among the groups. CONCLUSIONS: This study demonstrates that lower leg Rmin is greater in young white men with a positive parental history of hypertension than those with a negative parental history. In African Americans with either positive or negative parental histories, lower leg Rmin is not different. This finding suggests that heredity may have a greater influence in white populations than in African Americans on the structural changes in resistance vessels. The study also suggests that African Americans have an earlier structural change in the resistance vessels compared with white people, regardless of a parental history of hypertension. This suggests that factors other than heredity are of importance in changing the structure of the resistance vessels.

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A hot and humid environment can be detrimental to race performance. Caffeine, on the other hand, has been shown to be an ergogenic aid for improving endurance performance. To examine the influence of caffeine ingestion on race performance during high heat stress, seven endurance trained competitive road racers aged between 23 and 51 years (five men, two women) performed three maximal effort 21-km road races outdoors in hot and humid conditions. The caffeine dose, randomly assigned in a double-blind fashion, consisted of either 0, 5, or 9 mg.kg-1 body mass. During each run, the subjects were allowed to drink water ad libitum at each 5-km point. Blood samples were obtained immediately before and after each run and analysed for changes in concentrations of Na+, K+, glucose, lactate, and hematocrit. Pre and postrun data were also collected for body mass and tympanic membrane temperature. Race times were not significantly different among the races or caffeine doses, with the average times within 1.1% of each other. In addition, none of the other variables measured varied significantly among the races or caffeine doses. In summary, caffeine intake did not affect race performance. Therefore it was concluded from our study that caffeine is not of ergogenic benefit in endurance races during high heat stress.

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We present a case in which kappa free light chains caused difficulty in interpreting classical urinary immunoelectrophoresis, but immunofixation electrophoresis (IFE) demonstrated the presence of a lambda-Bence Jones protein. Analysis of the urine by Ouchterlony double diffusion and IFE after gel-filtration chromatography showed that the difficulty was caused by the presence of large amounts of polyclonal free light chains. The workup also demonstrated that although IFE is the more sensitive and specific technique, IFE performed on concentrated urinary samples is especially subject to misinterpretation unless densely staining patterns are diluted and reassayed. This process of sample dilution provides a means for titrating antigen and antibody concentrations such that condition-specific patterns become visible on the gel. This workup also shows that, at some dilutions, polyclonal free light chains may migrate in the same manner as an oligoclonal band in a so-called ladder configuration. These bands were observed from both monomeric and dimeric fractions isolated by gel chromatography, consistent with reports that this pattern is largely linked to the isoelectric points of the molecules. We speculate that, in rare instances, the distinction between polyclonal and monoclonal kappa free light chains migrating as a ladder-banding pattern may be equivocal.

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An automated electrophoretic method to measure glycated hemoglobin (Hb A1) was compared with manual affinity methods. Good correlation between methods was found. The electrophoretic method showed good run-to-run precision, good linearity, was free from interference by the labile aldimine fraction, and required less time and considerably less consumable expense than the affinity methods. However, as previously reported, Hb F comigrating with Hb A1 caused spurious increases in glycated Hb levels as compared with the affinity methods. This effect was linearly dependent on the Hb F concentration. Using the discrepancy between concentrations of Hb A1 by electrophoresis and glycated hemoglobin by affinity methods, 330 patients were screened in two hospitals for Hb F. A 12% frequency of elevated Hb F (defined as a level that is more than 2%) was found in patients from a community-tertiary care hospital, which is significantly greater than the 1.5% frequency commonly thought to occur in the adult population at large, whereas patients from a Veterans Administration Hospital showed an elevated frequency of 2.2%. Based on this and other studies, it is concluded that the frequency of elevated Hb F in adults may very substantially among different medical centers. The authors recommend against using this method and suggest that laboratories that persist in using it should periodically assess the frequency in patients with Hb F levels greater than 2% of total hemoglobin, replacing the method if an unacceptably high frequency is found.

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Policy development with regard to the shelf life of multidose medication vials is difficult because of a lack of sufficient data. The purpose of this study was to evaluate one factor that may play a role in the contamination of multidose vials. We evaluated the effect that the number of withdrawals had on the potential contamination of multidose medication vials. Thirty multidose vials of heparin and 30 multidose vials of lidocaine (lignocaine) were used in the study. Ten vials from each group (heparin and lidocaine) were used as controls and were deliberately contaminated with Staphylococcus aereus at various concentrations (10 colony forming units per millilitre (CFU/ml) to 10(8) CFU/ml). The 20 test vials remaining from each group were then subjected to varying rates of 1-ml fluid withdrawal. Five test vials were sampled every 2 h, five were sampled twice per day, five were sampled once per day, and five were sampled every other day. Each sample was incubated in trypticase soy broth (24 h at 37 degrees C) and Columbia agar with 5% sheep blood (48 h at 37 degrees C). No multidose vials became contaminated regardless of the rate of withdrawals. Some of the deliberately contaminated multidose vials became sterile with time. Lightly contaminated vials (10(1)-10(2) CFU/ml) generally cleared within 10-15 h after initial contamination. The implications of these findings are discussed.

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Fibrin glue is composed of two separate solutions of fibrinogen and thrombin. When mixed together, these agents mimic the last stages of the clotting cascade to form a fibrin clot. Fibrin glue is available in Europe but is not commercially available in the U.S.; therefore, investigators have extemporaneously compounded their own fibrin glue. Fibrinogen can be obtained from pooled, single-donor, and autologous blood donors and is usually isolated by the process of cryoprecipitation. The thrombin component is generally derived from commercial bovine sources. Some investigators have added calcium chloride and/or antifibrinolytics (i.e., aminocaproic acid, aprotinin) to their preparations. Fibrin glue can be applied using a double-barrel syringe or by spray application. Although fibrin glue has been used in a variety of surgical procedures, it has been especially useful in heparinized patients undergoing cardiovascular procedures requiring extracorporeal circulation, as it does not require an intact hemostatic system to be effective. Fibrin glue also has been evaluated in presealing woven or knitted Dacron vascular grafts. The major drawback to its use is the risk of transmitted serological disease from pooled and single-donor blood donors. The safest preparations use the patient's own blood to prepare fibrin glue. Overall, fibrin glue is a useful adjunct to other methods to control bleeding in selected surgical patients.

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Pralidoxime chloride is a useful agent in the treatment of organophosphate poisoning. Poisindex, a widely used poisoning treatment resource, recommends dosing pralidoxime chloride as an intermittent iv infusion every 8-12 hours, whereas other authors have used continuous iv infusion with good results. Available animal data suggest that a serum concentration of 4 micrograms/ml may be a minimal level to protect against the toxic effects of organophosphates. Pharmacokinetic simulations, based on parameters obtained from healthy nonpoisoned subjects, show that pralidoxime levels fall rapidly to less than 4 micrograms/ml within 1.5-2 hours after a 1-g iv bolus. Continuous iv infusion (0.5 g/h) maintains pralidoxime levels greater than 4 micrograms/ml throughout the length of infusion. We conclude that continuous iv infusion of pralidoxime chloride may be the preferred method of administration in patients with acute organophosphate poisoning. Clinical trials will be necessary to document the effectiveness of this regimen.

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The occurrence of Boophilus microplus infections accompanied by bovine babesiosis was confirmed for 2 locations in northern Mexico. The confirmation at one location was made by transferring whole blood to a splenectomised calf which subsequently developed an acute Babesia bovis infection. Examination of thin blood smears from a suspect animal at the second location revealed B. bovis-infected erthrocytes. A serological survey of other herd members at both locations showed antibody activity against both Babesia and Anaplasma spp.

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