Role of Technology for the Management of AKI in Critically Ill Patients: From Adoptive Technology to Precision Continuous Renal Replacement Therapy.

This paper reports on the continuous renal replacement therapy (CRRT) technology group recommendations and research proposals developed during the 17th Acute Dialysis Quality Initiative Meeting in Asiago, Italy. The group was tasked to address questions related to the impact of technology on acute kidney injury management. We discuss technological aspects of the decision to initiate CRRT and the components of the treatment prescription and delivery, the integration of information technology (IT) on overall patient management, the incorporation of CRRT into other 'non-renal' extracorporeal technologies such as ECMO and ECCO2R and the use of sorbents in sepsis and propose new areas for future research. Instead of reviewing current knowledge, the group focused on developing a renovated research agenda that reflects current and future technological advances, centered on innovations in new equipment, membranes and IT that will permit the integration of patient care and decision-making processes for years to come.

Defensive function of herbivore-induced plant volatile emissions in nature.

Herbivore attack is known to increase the emission of volatiles, which attract predators to herbivore-damaged plants in the laboratory and agricultural systems. We quantified volatile emissions from Nicotiana attenuata plants growing in natural populations during attack by three species of leaf-feeding herbivores and mimicked the release of five commonly emitted volatiles individually. Three compounds (cis-3-hexen-1-ol, linalool, and cis-alpha-bergamotene) increased egg predation rates by a generalist predator; linalool and the complete blend decreased lepidopteran oviposition rates. As a consequence, a plant could reduce the number of herbivores by more than 90% by releasing volatiles. These results confirm that indirect defenses can operate in nature.

Oak leaf quality declines in response to defoliation by gypsy moth larvae.

Leaves of red oak trees that had been defoliated by gypsy moth larvae during the previous year and again during the period of the study had higher values of tanning coefficients, total phenolics, hydrolyzable and condensed tannins, dry matter contents, and toughness than did leaves of undamaged trees. These changes may influence larval growth and alter the course of further outbreaks.

Rapid changes in tree leaf chemistry induced by damage: evidence for communication between plants.

Potted poplar ramets showed increased concentrations and rates of synthesis of phenolic compounds within 52 hours of having 7 percent of their leaf area removed by tearing, as did undamaged plants sharing the same enclosure. Damaged sugar maple seedlings responded in a manner similar to that of the damaged poplars. Nearby undamaged maples had increased levels of phenolics and hydrolyzable and condensed tannin within 36 hours, but exhibited no change in rates of synthesis. An airborne cue originating in damaged tissues may stimulate biochemical changes in neighboring plants that could influence the feeding and growth of phytophagous insects.

Phenotypic, genetic and genomic consequences of natural and synthetic polyploidization of Nicotiana attenuata and Nicotiana obtusifolia.

BACKGROUND AND METHODS: Polyploidy results in genetic turmoil, much of which is associated with new phenotypes that result in speciation. Five independent lines of synthetic allotetraploid N. x obtusiata (N x o) were created from crosses between the diploid N. attenuata (Na) (male) and N. obtusifolia (No) (female) and the autotetraploids of Na (NaT) and No (NoT) were synthesized. Their genetic, genomic and phenotypic changes were then compared with those of the parental diploid species (Na and No) as well as to the natural allotetraploids, N. quadrivalvis (Nq) and N. clevelandii (Nc), which formed 1 million years ago from crosses between ancient Na and No. KEY RESULTS: DNA fingerprinting profiles (by UP-PCR) revealed that the five N x o lines shared similar but not identical profiles. Both synthetic and natural polyploidy showed a dosage effect on genome size (as measured in seeds); however, only Nq was associated with a genome upsizing. Phenotypic analysis revealed that at the cellular level, N x o lines had phenotypes intermediate of the parental phenotypes. Both allo- and autotetraploidization had a dosage effect on seed and dry biomass (except for NaT), but not on stalk height at first flower. Nc showed paternal (Na) cellular phenotypes but inherited maternal (No) biomass and seed mass, whereas Nq showed maternal (No) cellular phenotypes but inherited paternal (Na) biomass and seed mass patterns. Principal component analysis grouped Nq with N x o lines, due to similar seed mass, stalk height and genome size. These traits separated Nc, No and Na from Nq and N x o lines, whereas biomass distinguished Na from N x o and Nq lines, and NaT clustered closer to Nq and N x o lines than to Na. CONCLUSIONS: Both allo- and autotetraploidy induce considerable morphological, genetic and genomic changes, many of which are retained by at least one of the natural polyploids. It is proposed that both natural and synthetic polyploids are well suited for studying the evolution of adaptive responses.

Resistance of vascular access catheters for continuous renal replacement therapy: An ex vivo evaluation.

AIM: To assess the resistance posed by double-lumen vascular access dialysis catheters at low and high blood flow. DESIGN: Controlled ex vivo study Setting: ICU Laboratory of tertiary hospital. SUBJECTS: Eleven proprietary vascular access catheters for continuous renal replacement therapy. METHODS: Heparinized spent red cells diluted in polygeline solution were pumped using the Aquarius hemofiltration machine (Edwards Life Sciences, Sydney, NSW, Australia) and its standard circuit through several vascular access catheters. Blood flow was increased and then decreased in steps of 50 ml/min (50, 150, 200, 250 and 300 ml/min) while catheter outflow and inflow pressures were recorded. The pressure-flow relationship (hydraulic resistance) of each catheter was then calculated. Study catheters were divided into two groups according to their internal diameter (large gauge vs. smaller gauge) or length (long or short). Hydraulic resistances were compared between the groups. RESULTS: Different double lumen catheters posed clearly different resistances to flow. For all groups of catheters, there was a linear relationship between pressure and flow. No statistically significant difference between short and long catheters could be demonstrated (p=0.715). On the other hand, larger gauge catheters (13 Fr or greater) had significantly lower resistances than smaller gauge (<13 Fr) catheters (p=0.0062). Furthermore, all larger gauge catheters had resistances lower than 0.430 mmHg/ml/min, while all smaller gauge catheters had resistances greater than 0.490 mmHg/ml/min. CONCLUSIONS: Commercial double-lumen dialysis catheters have variable resistance to blood flow under standard ex vivo conditions. Although both length and internal diameter varied, internal diameter had a dominant effect on resistance. This information might be useful to clinicians in guiding their choice of catheters for clinical use.

The acid-base effect of changing citrate solution for regional anticoagulation during continuous veno-venous hemofiltration.

PURPOSE: To compare the acid-base balance effects of two different citrate doses for regional citrate anticoagulant (RCA) for continuous veno-venous hemofiltration (CVVH). METHODS: We used a commercial citrate fluid (citrate concentration: 11 mmol/L) from July 2003 to July 2004 (period A) in 22 patients; then changed to a new citrate fluid (citrate concentration: 14 mmol/L) from July 2004 to Feb 2005 (Period B) in 21 patients. Replacement fluid rate was fixed at 2,000 ml/h. We measured all relevant variables for acid-base analysis according to the Stewart-Figge methodology. RESULTS: After commencement of RCA-CVVH, there was a change in bicarbonate and base excess (BE) toward acidosis for both fluids. This change was significantly different between period A and B at 6 and 12 hours (pH: p<0.01, BE: p<0.05) with greater decreases with the 11 mmol/L citrate fluid. These changes were mostly secondary to an increase in the strong ion difference (SID) and occurred despite an increased strong ion gap (SIG) (+0.5 mEq/L vs. +1.5 mEq/L; p<0.01) in the higher citrate concentration fluid. Cessation of RCA-CVVH was associated with short-lived differences in bicarbonate and SIG which were similar to those seen on initiation of RCA-CVVH but in the opposite direction. CONCLUSIONS: A small increase This was partly offset by an increase in SIG, consistent with increased citratemia. Cessation of treatment showed a differential improvement in SIG also consistent with disposal of therapy-associated citrate. These observations might assist clinicians in interpreting acidbase changes during RCA-CVVH.in citrate infusion rate caused an alkalinizing increase in SID.

The effect of three different miniaturized blood purification devices on plasma cytokine concentration in an ex vivo model of endotoxinemia.

PURPOSE: A novel type of adsorptive plasma filtering device (ETX-A) capable of removing endotoxin from blood in a single step has recently been developed using nanotechnology. METHODS: In a miniaturized, ex vivo model of extracorporeal circuits, we tested the capacity to reduce plasma cytokine concentration of ETX-A filters in comparison to standard high-flux (HF) filters, high cut-off (HCO) filters and a control. Blood from six healthy volunteers was spiked with endotoxin and then circulated through closed (ETX-A, control) or open (HF, HCO) circuits. Blood flow was set at 16 ml/min and filtration flow at 1 ml/min. Samples for measurement of IL-1ra and IL-6 were taken at baseline and at 4 hours. RESULTS: Compared to control (703.3 [850.6] pg/mL), in HCO (383.5 [1144.1] pg/mL) and ETX-A (490.1 [683.2] pg/mL) filters, plasma IL-1ra pooled pre- and postfilter concentrations were lower at the end of the experiment (P=0.002; P=0.050, respectively) whereas, in standard HF filters, IL-1ra concentration was higher than control. HCO showed a trend toward a reduced relative increase in IL-6 concentration from commencement to end of experiment compared to control (P=0.07). After pooling end-of-experiment plasma cytokine values of novel blood purification devices, we found HCO + ETX-A superior to H with regard to reduction of IL-1ra (-27.0 [-20.5]% vs. 8.1 [18.9]%; p<0.001) and IL-6 (-18.0 [38.3]% vs. -1.1 [24.3]%; P=0.050) compared to control. CONCLUSIONS: HCO and ETX-A appeared to significantly reduce plasma IL-1ra and, when combined, plasma IL-6 concentration as well. It appears desirable to manufacture full-size blood purification devices using this technology and to explore their effect on cytokine removal.

Fluid balance error in continuous renal replacement therapy: a technical note.

BACKGROUND: The reliability and safety of continuous renal replacement therapy (CRRT) machines have improved, yet there still remains the potential for fluid balance errors to occur during treatment. METHODS: In vitro testing of two Kimal Hygieia CRRT machines (Plus and Ultima) was performed. Normal saline to simulate the blood circuit and standard bicarbonate-based fluid for replacement were used. All tests were performed in CVVH mode at four ultrafiltration (UF) rates. The testing was based on creation of a voluntary fluid balance error by clamping the line that fills the replacement fluid chamber to stop flow to the (simulated) patient. The time to alarms and fluid balance errors were recorded. The alarms were overridden and the accumulated fluid balance error allowed by the machine was determined. RESULTS: The alarm occurred approximately 1 minute after the replacement fluid line was clamped at all UF rates. There was no limit to the number of times the alarm could be overridden and the accumulated negative fluid balance was proportional to the prescribed UF rate. After the replacement fluid chamber was allowed to re-fill, the machine attempted to correct the fluid deficit and consistently delivered excess fluid to generate a positive fluid balance error. CONCLUSIONS: The Hygieia machines appear designed with appropriate alarm and safety features. However, simulated fluid balance errors raise caution for operators. Clinicians and nurses need to understand the clinical implications of alarm overrides. Fluid balance errors caused by failure to acknowledge and correct replacement fluid failure alarms may cause harm to patients.

A pilot randomized controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemofiltration.

OBJECTIVE: To evaluate the efficacy and safety of a regional heparinization and a regional citrate method of anticoagulation in CVVH. DESIGN: Randomized controlled cross-over study. SUBJECTS: Ten critically ill patients with acute renal failure. SETTING: ICU of tertiary hospital. INTERVENTION: CVVH was performed with pre-filter fluid replacement at 2000 ml/h and a blood flow rate of 150 ml/min. Regional heparinization was by the administration of heparin pre-filter at 1500 IU/h and protamine post-filter at 15 mg/h. Regional citrate anticoagulation was by means of a citrate-based replacement fluid (14 mmol/L) administered pre-dilution. RESULTS: We studied nine males and one female. The mean age and APACHE II score were 70.5 and 17 respectively. Median circuit life was 13 hours (IQR 9.28) for the regional heparinization method compared to 17 hours (IQR 12,19.5) for the regional citrate method (p=0.77). There were no episodes of bleeding in either group. CONCLUSION: Regional heparinization and regional citrate anticoagulation achieve similar circuit life in critically ill patients receiving CVVH.

High cut-off point membranes in septic acute renal failure: a systematic review.

OBJECTIVES: To review the literature on the experimental, physiological and clinical effects of blood purification with high cut-off (HCO) point membranes in septic acute renal failure (ARF). STUDY DESIGN: MEDLINE and PubMed database search combining relevant terms and integrating data from studies on the use of HCO membranes. SETTING AND POPULATION: Ex vivo studies of endotoxemia, animal studies of bacteremia and clinical studies using HCO membranes in patients with septic ARF. SELECTION CRITERIA FOR STUDIES: Original data from primary publications. INTERVENTIONS: HCO membrane-based hemodialysis, hemodiafiltration or hemofiltration. OUTCOMES: Plasma cytokine clearance, immunological and physiological effects and safety parameters of HCO membranes. RESULTS: HCO membranes effectively remove cytokines from blood. Treatment using HCO membranes has beneficial effects on immune cell function and increases survival in animal models of sepsis. Preliminary clinical studies show that HCO membranes decrease plasma cytokine levels and the need for vasopressor therapy. HCO membrane-based blood purification has now been applied in four pilot randomized controlled studies of 70 patients with septic ARF with no reports of serious adverse effects. LIMITATIONS: Because of substantial heterogeneity, no formal quantitative analysis could be performed. CONCLUSIONS: The available evidence on HCO blood purification justifies larger randomized controlled trials in patients with septic ARF.

A pilot randomized controlled comparison of extended daily dialysis with filtration and continuous veno-venous hemofiltration: fluid removal and hemodynamics.

OBJECTIVES: Extended intermittent dialytic techniques are increasingly being reported in the treatment of ARF in the ICU but few randomized controlled trials exist. We compared one such technique to a technique of continuous renal replacement therapy with regard to fluid removal and hemodynamics. METHODS: Sixteen critically ill patients with ARF were enrolled in a randomized controlled trial at the ICU of a tertiary hospital. We randomized eight patients to three consecutive days of treatment with either Extended Daily Dialysis with filtration (EDDf) or Continuous Veno-Venous Hemofiltration (CVVH) and compared fluid removal and hemodynamics during treatment. RESULTS: A total of 16.6 liters of fluid were removed during EDDf (830 mL/day over 20 treatment days) compared with 15.4 liters (700 ml/day over 22 treatment days) during CVVH. Median fluid removal per day was 1837 mL in the EDDf group compared with 1410 mL per day in the CVVH group, p=0.674. Median hourly fluid removal rate was 252 mL for EDDf and 128 mL for CVVH (p<0.01). Mean arterial pressure in the EDDf group was lower at two hours after starting treatment (76 mmHg vs. 94 mmHg) in the CVVH group; p= 0.031. There was no significant difference between groups for heart rate, CVP and noradrenaline dose at all time intervals measured. CONCLUSIONS: Adequate prescribed fluid removal was achieved with both techniques. However, as expected, fluid was removed at a faster rate during EDDf. This was initially associated with a lower blood pressure than during CVVH where blood pressure increased.

Beta2-microglobulin removal and plasma albumin levels with high cut-off hemodialysis.

PURPOSE: beta2-microglobulin (beta2MG) is pivotal to the pathogenesis of dialysis-related amyloidosis. We compared the effects of high cut-off hemodialysis (HCO-HD) with those of standard high-flux hemodialysis (HF-HD) regarding the concentration and clearance of beta2MG and albumin. DESIGN: We enrolled ten patients with acute renal failure in a double-blind, cross-over, randomized controlled trial. PROCEDURES: Each patient received four hours of HCO-HD (estimated in vivo cutoff 50-60 kDa) and four hours of HF-HD (estimated in vivo cutoff 15-20 kDa) in random order. Statistical methods and outcome measures: As data lacked normal distribution, we used nonparametric statistical analysis. Plasma and dialysate concentrations of beta2MG and albumin were measured at baseline and after four hours of each study treatment. MAIN FINDINGS: We found significantly greater diffusive beta2MG clearances for HCO-HD compared to HF-HD (at the start: 71.8 ml/min vs. 5.1 ml/min; P=0.008 and at the end: 68.8 ml/min vs. 5.7 ml/min; P=0.008). We found a reduction in plasma beta2MG concentrations of -31.6% during HCO-HD compared to an increase by 25.7% during HF-HD; P=0.008. At baseline (HCO-HD: 26.0 g/L vs. HF-HD: 26.5 g/L), and at the end of both treatments, plasma albumin concentrations were comparable (HCO-HD: 25.5 g/L vs. HF-HD: 26.5 g/L; P=0.25). During HCO-HD, albumin clearance was 1.9 ml/min at the start and decreased significantly to 0.8 ml/min at the end; P=0.008. HF-HD had an albumin clearance of 0.01 ml/min. CONCLUSIONS: HCO-HD was more effective in decreasing plasma beta2MG concentrations than standard HF-HD and did not reduce plasma albumin levels. Further studies of HCO-HD in the treatment of dialysis-related beta2MG accumulation appear warranted.

Merging molecular and ecological approaches in plant-insect interactions.

The singer-song-writer Paul Simon sang about the '50 ways to leave your lover'; plants have at least as many ways of coping with their insect herbivores. Recent research has elucidated the mechanisms of direct and indirect plant defenses, and has provided the first proof of a protective function for indirect defenses in nature. Insect attack elicits a large transcriptional reorganization that differs from that elicited by mechanical wounding. Elicitors in herbivore oral secretions can account for herbivore-specific responses. Patterns of transcriptional changes point to the existence of central herbivore-activated regulators of metabolism.

Management of fluid balance in CRRT: a technical approach.

BACKGROUND: The possibility of making fluid balance errors during continuous renal replacement therapy has been identified since the beginning of this modality of treatment. The advent of automated machines has partially overcome this problem. Nevertheless, there are conditions and operation modes in which the potential for fluid balance errors is still present. OBJECTIVE: To analyse fluid balance management in CRRT therapies across a range of currently marketed machine. METHODS: The tests were conducted in vitro, utilizing saline solution for the blood circuit and regular dialysate/reinfusate for the dialysate/reinfusion circuit. The methodology used was based on the voluntary creation of a fluid balance error by altering the correct flow in the circuit of the different machines. Subsequently, the time for alarm occurrence and the threshold value for fluid balance error was evaluated. The alarm was overridden and the overall fluid error allowed by the machine was evaluated. Each machine was tested in conditions of different dialysate/filtrate flow rates and in different simulated treatment modalities. RESULTS: Fluid balance errors can be easily avoided not only by a correct and careful adherence to the protocols of use of the current CRRT machines, but also by the compliance to prescriptions and programmed controls during therapy. Most importantly, if an alarm appears on the machine, one can try to override it without major problems; major problems may occur when multiple override commands are operated without identifying the problem and solving it adequately. CONCLUSION: Machines seem to be designed with adequate safety features and accurate alarm systems. However, features and alarms can be manipulated by operators creating the opportunity for serious error. Physicians and nurses involved in prescription and delivery of CRRT should have precise protocols and defined procedures in relation to machine alarms to prevent major clinical problems.

Low-dose citrate continuous veno-venous hemofiltration (CVVH) and acid-base balance.

OBJECTIVE: To evaluate the acid-base effect of low-dose regional citrate anticoagulation (RCA) during continuous veno-venous hemofiltration (CVVH). DESIGN: Prospective observational study. SETTING: ICUs of tertiary public and private hospitals. SUBJECTS: Thirty critically ill patients with acute renal failure at risk of bleeding or with a major contraindication to heparin-CVVH and/or short filter life. METHODS: We used a commercial citrate-based fluid (11 mmol/L, sodium: 140 mmol/L, chloride: 108 mmol/L and 1 mol/L of potassium) as pre-dilution replacement fluid during CVVH. Further potassium was added according to serum potassium levels. We measured all relevant variables for acid-base analysis according to the Stewart-Figge methodology. RESULTS: Before treatment, study patients had a slight metabolic acidosis, which worsened over 6 hours of RCA-CVVH (pH from 7.39 to 7.38, p < 0.005; bicarbonate from 23.2 to 21.6 mmol/L, p < 0.0001 and base excess from -2.0 to -3.0 mEq/L, p < 0.0001) due to a significant increase in SIG (from 5.8 to 6.6 mEq/L, p < 0.05) and a decrease in SIDa (from 37.5 to 36.6 mEq/L, p < 0.05). These acidifying effects were attenuated by hypoalbuminemia and a decrease in lactate (from 1.48 to 1.34 mmol/L, p < 0.005) and did not lead to progressive acidosis. On cessation of treatment, this acidifying effect rapidly self-corrected within six hours. CONCLUSIONS: Low dose RCA-CVVH induces a mild acidosis secondary to an increased strong ion gap and decreased SIDa which fully self-corrects at cessation of therapy. Clinicians need to be aware of these effects to correctly interpret changes in acid-base status in such patients.

A comparison of two citrate anticoagulation regimens for continuous veno-venous hemofiltration.

AIMS: To assess the safety and efficacy of two different commercial citrate containing pre-filter replacement fluids during continuous veno-venous hemofiltration (CVVH) in patients with frequent filter clotting. SETTING: Four intensive care units. PATIENTS: Sixty-three critically ill patients with acute renal failure (ARF). DESIGN: Prospective observational study. METHODS: We used a commercial citrate fluid (citrate: 11 mmol/L -fluid A) as predilution replacement for CVVH. We then changed to a new commercial citrate fluid (citrate: 14 mmol/L-fluid B) as replacement fluid and performed statistical comparisons. Replacement fluid rate was fixed at 2,000 ml/hour. RESULTS: Filter life was 12.2 hour with fluid A compared with 17.1 hour with fluid B on average (p=0.0001). Mean post filter ionized calcium concentration was 0.52 mmol/L with fluid A compared with 0.40 mmol/L with fluid B (p<0.0001). Citrate intolerance led to cessation of treatment in one patient with fluid A and one patient with fluid B. Overall ionized calcium levels were higher (A: 1.18 vs B: 1.13 mmol/L; p<0.0001) and bicarbonate was lower (A: 22.4 vs B: 24.5 mmol/L; p<0.0001) during treatment with fluid A. Alkalemia was seen in 10 patients treated with fluid A and 16 patients treated with fluid B (NS). CONCLUSIONS: We have developed a simple approach to regional citrate anticoagulation for CVVH using a commercial citrate-containing fluid as replacement fluid. Increasing citrate concentration from 11 to 14 mmol/L increased filter life while maintaining relative safety and simplicity.

[Long-term intermittent renal replacement therapy at an intensive care unit].

Standard intermittent hemodialysis (IHD) used for the treatment of acute renal failure (ARF) at an intensive care unit has significant biochemical and physiological drawbacks. In the past 20 years, these drawbacks have stimulated the development of continuous renal replacement therapy (CRRT) and its ever-increasing use. However, CRRT is technically complicated and requires 24-hour monitoring. In some clinics, the use of CRRT leads to that each patient is under his/her nurse's surveillance, instead 1 nurse per 2 patients as before; this change has economic consequences and may limit nursing accessibility to other patients. The procedures prolonging intermittent therapy do not require 24-hour monitoring may benefit the treatment of ARF at the intensive care therapy. In this paper the authors call such procedures for continuous intermittent renal replacement therapy. They are characterized by a number of basic principles: (1) the use of modified or standard dialysis apparatuses; (2) the application of diffuse, convection, or both; (3) a certain reduction in the rate of elimination of dissolved substances as compared with IHD; (4) more prolonged treatment: above usual 3 or 4 hours of IHD, but not more than 8-12 hours (hence the term "intermittent"); (5) the use of on-line generation dialysate or substituting fluid. Information on the effectiveness and safety of this procedure is being now compiled.

Functional interactions in the use of direct and indirect defences in native Nicotiana plants.

Nicotiana attenuata has both direct (induced nicotine production) and indirect (induced release of mono- and sesquiterpenes) defences induced by herbivore attack; both are activated by the jasmonate cascade, albeit in different tissues (roots and shoots, respectively). The fact that both types of defences are induced suggests that their benefits are conditional. Indeed, jasmonate treatment of roots to induce nicotine production increases plant fitness correlates (lifetime viable seed production) when plants are grown in environments with herbivores, but decreases fitness when they are not. Because inducing nicotine production can make 6% of a plant's nitrogen budget unavailable for seed production, it can exact a resource-based cost. Volatile production is likely to be less costly but could make plants more 'apparent' to herbivores and thereby exact an ecological cost. Direct defences could also have ecological costs if they are sequestered by specialist herbivores and used against their enemies. Herbivory by the nicotine-tolerant herbivore Manduca sexta dramatically amplifies the increase in jasmonates and the quantity of volatiles released, but decreases the nicotine response in comparison to mechanical simulations of the wounding that larval feeding causes. The apparent switching from nicotine production to the release of volatiles may reflect incompatibilities in the use of direct and indirect defences with specialist herbivores.

Synthesis of enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines by phenylsulfanyl migration.

[reaction: see text] Enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines can be prepared, in high overall yield, from alpha,beta-unsaturated esters. Asymmetry is introduced via a Michael addition, and additional stereogenic centers are introduced by an aldol reaction. A novel stereospecific ring-forming reaction, proceeding via a thiiranium (episulfonium) ion, yields pyrrolidines from beta-hydroxy sulfides. In this manner, 2,2,3,4,5-pentasubstituted pyrrolidines, containing three contiguous stereogenic centers around the ring, can be prepared in 44% overall yield from ethyl crotonate.