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Anthelmintic resistance by gastrointestinal nematodes of sheep continues to be an issue of global interest. While the recent introduction in some countries of one or two new anthelmintic classes (amino-acetonitrile derivatives [AAD] and spiroindoles [SI]) has been welcomed, it is important that there is no relaxation in parasite control and the management of drug resistance. Monepantel (an AAD) was the first new anthelmintic to be approved for use (New Zealand, 2009) and was followed a year later in the same country by a combination of derquantel (a SI) and abamectin. The present study determined the efficacy of the new anthelmintic products and abamectin against fourth-stage larvae of macrocyclic lactone-resistant Teladorsagia spp. in lambs. Efficacies were calculated by comparing post-mortem nematode burdens of treated animals with those of untreated control sheep, and were 98.5, 86.3 and 34.0% for monepantel, abamectin/derquantel and abamectin, respectively. The nematode burdens of monepantel- and abamectin/derquantel-treated sheep were significantly lower than those sheep treated with abamectin and the untreated controls. Similarly, the burden of the monepantel group was significantly lower than that of the abamectin/derquantel group. These findings provide an opportunity to reinforce the recommendation that farmers and animal health advisors need to know the resistance status of nematode populations on subject farms to ensure effective control programs are designed and implemented. Such control programs should include an appropriate choice of anthelmintic(s), monitoring parasite burdens for correct timing of treatments, and pasture management to reduce larval challenge balanced with the maintenance of drug-susceptible populations in refugia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Three experiments defined the resistance profile of a population of Haemonchus contortus, which was shown to express multiple resistances to the benzimidazole, levamisole, macrocyclic lactone and salicylanilide anthelmintic classes when given as a registered combination. Study 1 was a faecal egg count reduction (FECR) test and the efficacies for the anthelmintics were monepantel, 100%; abamectin+levamisole+oxfendazole, 40.0%; and abamectin+levamisole+oxfendazole+naphthalophos, 100%. No larvae were recovered from the post-treatment cultures for monepantel or the 4-way treatment, and for the 3-way treatment the culture was 100% Haemonchus spp. Efficacies in Study 2 were calculated from mean post-mortem nematode burdens of H. contortus and were levamisole+oxfendazole, 3.1%; abamectin+levamisole+oxfendazole, 5.0%; ivermectin, 0.4%; moxidectin, 28.4% and closantel, 70.2%. Study 3 was also a FECR test that resulted in efficacies of 100% for monepantel and 83.0% for a formulated 4-way combination of abamectin+levamisole+albendazole+closantel. Larvae recovered from the post-treatment culture for the combination-treated sheep were all Haemonchus spp. Multi-resistant parasites such as examined in these studies are a continuing challenge to be managed by farmers and their advisors. Control programs must be planned and well-managed, and should include on-farm testing for anthelmintic resistance, monitoring of nematode burdens (by FEC and larval culture) to determine appropriate treatment times and the management of pastures to reduce the overall parasite challenge. This should be in balance with the generation, use and maintenance of drug-susceptible nematode populations in refugia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

As it has been 30 years since a new anthelmintic class was released, it is appropriate to review management practices aimed at slowing the development of anthelmintic resistance to all drug classes. Recommendations to delay anthelmintic resistance, provide refugia and the use of a simulation model were reviewed to find optimum treatment strategies that maintain nematode control. Simulated Australian conditions indicated that a common successful low-risk treatment program was a rapid rotation between a "triple-combination" product (benzimidazole+levamisole+abamectin) and a new high-efficacy drug (monepantel). Where Haemonchus contortus was a threat, moxidectin was required at critical times because of its persistent activity against this parasite. Leaving up to 4% of adult sheep untreated provided sufficient "refugia" for non-selected worms to reduce the risk of selecting for anthelmintic resistance without compromising nematode control. For a new anthelmintic, efficacy estimated by faecal egg count reduction (FECR) is likely to be at or close to 100%, however using current methods the 95% confidence limits (CL) for 100% are incorrectly determined as 100%. The fewer eggs counted pre-treatment, the more likely an estimate of 100% will occur, particularly if the true efficacy is >90%. A novel way to determine the lower-CL (LCL) for 100% efficacy is to reframe FECR as a binomial proportion, i.e. define: n and x as the total number of eggs counted (rather than eggs per gram of faeces) for all pre-treatment and post-treatment animals, respectively; p the proportion of resistant eggs is p = x/n and percent efficacy is 100 ×(1-p) (assuming equal treatment group sizes and detection levels, pre- and post-treatment). The LCL is approximated from the cumulative inverse beta distribution by: 95%LCL=100 ×(1-(BETAINV(0.975, x+1, n-x+1))). This method is simpler than the current method, independent of the number of animals tested, and demonstrates that for 100% efficacy at least 37 eggs (not eggs per gram) need to be counted pre-treatment before the LCL can exceed 90%. When nematode aggregation is high, this method can be usefully applied to efficacy estimates lower than 100%, and in this case the 95% upper-CL (UCL) can be estimated by: 95% UCL = 100 ×(1((BETAINV(0.025, x+1, n-x+1))), with the LCL approximated as described above. A simulation study to estimate the precision and accuracy of this method found that the more conservative 99%CL was optimum; in this case 0.975 and 0.025 are replaced by 0.995 and 0.005 to estimate the LCL and UCL, respectively., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A controlled, blinded study was undertaken in 6-week old, pre-weaned lambs to demonstrate the safety and efficacy against fourth-stage gastrointestinal nematode larvae, of monepantel administered per os at 2.5mg/kg body weight. Worm burdens of 10 monepantel-treated lambs were compared to those from 10 untreated control lambs. Geometric mean derived efficacies of 100, 100, 96.4 and 99.9% were demonstrated against Haemonchus contortus, Teladorsagia spp., Cooperia curticei and Trichostrongylus colubriformis, respectively. These results, considered in the light of an earlier series of studies demonstrating the efficacy of monepantel in older animals, and an absence of any adverse events, provides strong support for the use of monepantel as a safe and effective anthelmintic in lambs from six weeks of age., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%).

Monepantel is the first molecule from the amino-acetonitrile derivatives to be developed for controlling gastro-intestinal nematodes in sheep. Two studies were undertaken to examine the drug's efficacy against inhibited fourth-stage larvae of Haemonchus contortus and Teladorsagia spp. in sheep when administered as an oral solution at 2.5mg/kg bodyweight. In study 1, efficacy was 99.7% against H. contortus (p<0.0001) and in study 2, 99.8% against Teladorsagia spp. (p<0.0001). This population consisted of 93% T. circumcincta and 7% T. trifurcata. In conclusion, monepantel is a highly effective treatment against inhibited fourth-stage larvae of H. contortus and Teladorsagia spp. and the studies reported here provide the first published evidence of efficacy of this new anthelmintic against these parasites., ((c) 2010 Elsevier B.V. All rights reserved.)

The effect of the route of administration (oral, intraruminal and intra-abomasal) on the efficacy and pharmacokinetics of the new anthelmintic monepantel in sheep was investigated. The target nematodes were fourth-stage Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis and Cooperia curticei. A clear difference in efficacy was identified between the routes of administration, although the difference did not consistently reach statistical significance; oral treatment was most effective, followed by intraruminal and then intra-abomasal administration. The same pattern was observed in the pharmacokinetic analysis, with lambs treated orally having more favourable exposure to monepantel and its sulfone metabolite (albeit in all but one instance not significantly different) than the lambs treated by the other routes of administration, which were very similar for most parameters.

Eighteen, six- to seven-month-old lambs were infected experimentally with larvae of Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei and Nematodirus spathiger, and allocated to three equal groups. The infections were timed to ensure that fourth-stage larvae were present when groups 1 and 2 were treated orally with monepantel. Group 1 was not fed for 24 hours before the treatment, group 2 was fed two hours before the treatment and group 3 was fed at the same time as group 2 but not treated with monepantel. All the sheep had access to water. Worm burdens were determined 15 days after the treatments. Fasting or feeding had no statistically significant effects on the efficacy of the monepantel solution against the nematodes, and the period of fasting had no adverse effects.

Monepantel is the first compound from the recently discovered amino-acetonitrile derivative (AAD) class of anthelmintics to be developed for use in sheep. Nine dose confirmation studies were conducted in Australia, New Zealand and Switzerland to confirm the minimum therapeutic oral dose of monepantel to control fourth stage (L4) gastro-intestinal nematode larvae in sheep (target species were Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Teladorsagia trifurcata, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus vitrinus, Cooperia curticei, Cooperia oncophora, Nematodirusbattus, Nematodirusfilicollis, Nematodirus spathiger, Chabertia ovina and Oesophagostomum venulosum). In each study, sheep infected with a defined selection of the target nematodes were treated with 2.5mg monepantel/kg liveweight. Following euthanasia and worm counting, efficacy was calculated against worm counts from untreated control groups. The results demonstrate high (95<100%) efficacy of monepantel when administered orally to sheep at 2.5mg/kg for most species tested. Efficacy levels against N. spathiger and O. venulosum were variable and failed to meet the required regulatory standard (> or =90%) in some studies. Efficacy was demonstrated against L4 stages of nematodes known to be resistant to either benzimidazole and/or levamisole anthelmintics (macrocyclic lactone resistant isolates were not available for testing). The broad-spectrum activity of monepantel against L4 larvae of common gastro-intestinal nematodes in sheep and its favorable safety profile represents a significant advance in the treatment of parasitic gastro-enteritis in this animal species. No adverse effects related to treatment with monepantel were observed.

Monepantel is the first compound from the recently discovered amino-acetonitrile derivative (AAD) class of anthelmintics to be developed for use in sheep. Three dose determination studies were conducted in Australia and Switzerland to identify the minimum therapeutic dose of monepantel when formulated for the oral treatment of sheep to control fourth stage (L4) gastro-intestinal nematode larvae. In each study, sheep infected with the target nematodes (selected from Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Teladorsagia trifurcata, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus vitrinus, Cooperia curticei, Cooperia oncophora, Nematodirus battus, Nematodirus filicollis, Nematodirus spathiger, Chabertia ovina and Oesophagostomum venulosum) were treated with either 1.25, 2.5 or 5.0 mg monepantel/kg liveweight. Following euthanasia and worm counting, efficacy was calculated against worm counts from untreated control groups. Monepantel proved highly effective at 2.5 and 5.0 mg/kg, but was only moderately effective against some nematode species (L4 stage) at 1.25 mg/kg. The results also confirmed that monepantel will effectively control L4 stages of nematodes resistant to at least some of the currently available broad-spectrum anthelmintic classes (macrocyclic lactone resistant strains were not included in the studies). It was concluded that 2.5 mg/kg would be a suitable minimum dose rate for a commercial product. No adverse events related to treatment with monepantel were detected.

Recent studies in Xenopus egg extracts indicate that the small G protein Ran has a central role in spindle assembly and nuclear envelope reformation. We determined Ran localization and dynamics in cells during M phase. By immunofluorescence, Ran is accumulated on the chromosomes of meiosis-II-arrested Xenopus eggs. In living cells, fluorescently labeled Ran associated with the chromosomes in Xenopus and remained associated during anaphase when eggs were artificially activated. Fluorescent Ran associated with chromosomes in mouse eggs, during meiotic maturation and early embryonic divisions in starfish, and to a lesser degree during mitosis of a cultured mammalian cell line. Chromosomal Ran undergoes constant flux. From photobleach experiments in immature starfish oocytes, chromosomal Ran has a k(off) of approximately 0.06 second(-1), and binding analysis suggests that there is a single major site. The chromosomal interactions may serve to keep Ran-GTP in the vicinity of the chromosomes for spindle assembly and nuclear envelope reformation.

The IVPro isolate of Haemonchus contortus was isolated in 1999 after significant numbers of the parasite survived an ivermectin capsule treatment of grazing sheep acquiring a natural infection at Prospect, NSW, Australia. The isolate shows high-level resistance to ivermectin (faecal egg count is unaffected by ivermectin oral treatment at 0.2mg kg(-1)). The larval LC(50), as assessed by larval development assays (LDAs), is only approximately two-fold higher than several susceptible isolates, making it difficult to detect the resistance using larval LC(50) as an indicator. However, the isolate shows the presence of a small proportion of the population (<20%) able to develop at significantly higher drug concentrations than the susceptible isolates. Hence, if the IVPro and susceptible isolates are compared at the LC(99) level, the IVPro isolate is readily identifiable as resistant. This degree of distinction at the LC(99) allows the IVPro isolate to be identified as resistant by simply observing the highest drug concentration in the development assay at which some larvae develop relative to the susceptible isolates. Assessing the development assay using this criterion allows a distinction between IVPro and the susceptible isolates equivalent to 10-fold differences in drug concentration, greatly increasing the likelihood of detecting the resistant isolate in routine resistance tests. This study highlights the need to examine this aspect of LDAs in order to detect the type of resistance displayed by IVPro H. contortus.

We have identified a novel mammalian protein, MIR1, with microtubule-binding activity. MIR1 is a relative of MID1/midin, the protein implicated in Opitz G/BBB syndrome. In tissue culture cells, MIR1 is enriched at the centrosome. MIR1 dissociates from centrosomes at the G2/M transition and is recruited back to spindle poles during anaphase. When overexpressed during interphase, MIR1 binds along microtubule filaments, which become stabilized, bundled and detached from the centrosome. In mitosis, overexpressed MIR1 dissociates from microtubules but still affects the normally focused localization of gamma-tubulin in spindle poles. Tight binding to microtubules in interphase appears to require an oligomeric state of MIR1, and phosphorylation in mitosis at predicted cyclin-dependent kinase (cdk) sites weakens the interaction.

The in vivo effects of ivermectin and moxidectin on egg viability and larval development of ivermectin-resistant Haemonchus contortus were examined over time after anthelmintic treatment of sheep. Twenty merino sheep, (12 months old) were allocated to five treatment groups and infected with ivermectin-resistant H. contortus. Thirty one days later, the sheep were treated with intraruminal ivermectin capsules, oral ivermectin, oral moxidectin or injectable moxidectin at the manufacturer's recommended dosages, or left untreated. At various times up to 112 days after treatment, faecal egg counts (FEC) were determined and development rates of infective larvae (L3) cultured in faeces or on agar were measured. Eggs in faecal cultures from ivermectin capsule treated sheep showed reduced L3 development percentages in comparison to faecal cultures from untreated sheep. Eggs from ivermectin capsule treated sheep, isolated from faeces, and cultured on agar showed similar L3 development to eggs from control sheep. These results demonstrate an inhibitory effect of excreted ivermectin in faeces on larval development of ivermectin-resistant H. contortus. L3 development in faecal culture from animals receiving oral ivermectin were reduced for only 3 days after treatment. Faecal egg counts and development of L3 larvae in both culture systems from moxidectin treated sheep were low, due to the high efficacy of the drug. Egg counts in moxidectin treated sheep were reduced by approximately 90% 24h after treatment, before decreasing to almost 100% at 48h, suggesting that the current quarantine recommendation of holding sheep off pasture for 24h after treatment may still lead to some subsequent pasture contamination with worm eggs.

To understand the factors that influence selection for anthelmintic resistance, it is necessary to examine the impact of drug treatment, particularly persistent drugs, on all phases of the worm life cycle. The efficacy of various avermectin/milbemycin anthelmintics was determined against resident worms, incoming larvae (L3) and development of eggs in faecal culture. Homozygote-resistant and maternal and paternal F1-heterozygote genotypes of Haemonchus contortus were used to infect sheep before or after treatment with ivermectin (IVM) oral, IVM capsule, moxidectin (MOX) oral or MOX injectable. Total worm count and quantitative larval culture were used to determine efficacy against parasitic and free-living stages, respectively. Selection for resistance by IVM capsules occurred at the adult and L3 stages because of poor efficacy against these stages for all resistant genotypes. However, the selective advantage of these surviving worms was reduced due to the low development of their eggs to L3 in faecal culture. For MOX, selection for resistance predominantly occurred after treatment because of high efficacy against resident adult worms of all resistant genotypes but poor efficacy against resistant L3 ingested after drug administration. The results indicated no evidence of sex-linked inheritance for IVM resistance. Mean IVM efficacies against homozygous and heterozygous resistant adult worms were not different, and IVM capsule efficacy against incoming L3 was approximately 70% for all resistant genotypes, consistent with a dominant trait. MOX was highly effective against adults of all resistant genotypes and approximately 76% effective against incoming L3 regardless of resistance genotype, also consistent with a dominant trait. These results will enable the impact of persistent drugs on worm control and anthelmintic resistance to be estimated. The results indicate that IVM capsules should not be used in populations where avermectin/milbemycin resistance is present.

Nuclear envelope breakdown was investigated during meiotic maturation of starfish oocytes. Fluorescent 70-kDa dextran entry, as monitored by confocal microscopy, consists of two phases, a slow uniform increase and then a massive wave. From quantitative analysis of the first phase of dextran entry, and from imaging of green fluorescent protein chimeras, we conclude that nuclear pore disassembly begins several minutes before nuclear envelope breakdown. The best fit for the second phase of entry is with a spreading disruption of the membrane permeability barrier determined by three-dimensional computer simulations of diffusion. We propose a new model for the mechanism of nuclear envelope breakdown in which disassembly of the nuclear pores leads to a fenestration of the nuclear envelope double membrane.

The nuclear envelope (NE) is a distinct subdomain of the ER, but few membrane components have been described that are specific to it. We performed a visual screen in tissue culture cells to identify proteins targeted to the NE. This approach does not require assumptions about the nature of the association with the NE or the physical separation of NE and ER. We confirmed that screening a library of fusions to the green fluorescent protein can be used to identify proteins targeted to various subcompartments of mammalian cells, including the NE. With this approach, we identified a new NE membrane protein, named nurim. Nurim is a multispanning membrane protein without large hydrophilic domains that is very tightly associated with the nucleus. Unlike the known NE membrane proteins, it is neither associated with nuclear pores, nor targeted like lamin-associated membrane proteins. Thus, nurim is a new type of NE membrane protein that is localized to the NE by a distinct mechanism.

Responses of several nematode species to naphthalophos and pyrantel/levamisole were examined using a larval development assay in order to determine the potential of this assay for detection of resistance. Haemonchus contortus and Ostertagia circumcincta showed concentration-dependent responses to naphthalophos, however, the assay was unsuitable for Trichostrongylus colubriformis due to the low toxicity of the drug to the larval stages of this nematode. Measurement of concentration-dependent response to pyrantel in susceptible T. colubriformis was limited by a reduced toxicity against larvae at high drug concentrations, resulting in a parabolic response with a development-inhibition maxima of less than 100%. This limits the usefulness of the assay to detect pyrantel resistance in this species as the presence of a small resistant fraction in a field isolate may be indistinguishable from the parabolic susceptible response. On the other hand, responses of susceptible T. colubriformis to levamisole, and susceptible H. contortus to pyrantel and levamisole showed 100% development inhibition over a range of drug concentrations, indicating that the appearance of a resistant fraction in a field population would be readily discernible from the susceptible response, allowing resistance detection for these drug/parasite combinations. This study has highlighted the varied suitability of the larval development assay technique for resistance detection with different combinations of drugs and parasite species.

We have examined the role of FGF signalling in the development of muscle and notochord and in the expression of early mesodermal markers in Xenopus embryos. Disruption of the FGF signalling pathway by expression of a dominant negative construct of the FGF receptor (XFD) generally results in gastrulation defects that are later evident in the formation of the trunk and tail, though head structures are formed nearly normally. These defects are reflected in the loss of notochord and muscle. Even in embryos that show mild defects and gastrulate properly, muscle formation is impaired, suggesting that morphogenesis and tissue differentiation each depend on FGF. The XFD protein inhibits the expression of the immediate early gene brachyury throughout the marginal zone, including the dorsal side; it does not, however, inhibit the dorsal lip marker goosecoid, which is expressed in the first involuting mesoderm at the dorsal side that will underlie the head. The XFD protein also inhibits Xpo expression, an immediate early marker of ventral and lateral mesoderm. These results suggest that FGF is involved in the earliest events of most mesoderm induction that occur before gastrulation and that the early dorsal mesoderm is already composed of two cell populations that differ in their requirements for FGF.

We have constructed a nuclear genomic library from the cruciferous plant Arabidopsis thaliana ecotype Columbia in a cosmid vector, pLZO3, and a host organism, Agrobacterium tumefaciens AGL1, which can directly DNA-transform the parent organism, Arabidopsis. The broad host range cosmid pLZO3 carries a gentamicin acetyltransferase gene as bacterial selective marker and tandem, chimeric neomycin and streptomycin phosphotransferase genes as plant selective markers. Agrobacterium AGL1 carries the hypervirulent, attenuated tumor-inducing plasmid pTiBo542 from which T-region DNA sequences have been precisely deleted, allowing optimal DNA transformation of many dicotyledonous plants. Agrobacterium AGL1 also carries an insertion mutation in its recA general recombination gene, which stabilizes the recombinant plasmids. The Arabidopsis genomic library consists of some 21,600 clones gridded onto 96-well microtiter dishes and, if random, carries at least three genomic equivalents. When probed for the presence of several Arabidopsis low copy-number genes, the genomic library seems representative. As with the unicellular organisms Escherichia coli and Saccharomyces cerevisiae, this DNA transformation competent genomic library should expedite gene isolation, by gene rescue, in multicellular organisms like Arabidopsis.

Manifest anxiety scores of students receiving part-time services for learning disabilities, students receiving full-time services for learning disabilities, and a matched group of nonexceptional peers were compared. A significant difference was found between the part-time group and the nonexceptional group in Total Anxiety and Worry-Oversensitivity.

From nucleotide sequencing analyses, the A. caulinodans nifA gene seems to be under dual control by the Ntr (in response to available N) and Fnr (in response to available O2) transcriptional activation/repression systems. Because it fixes N2 in two contexts, the Ntr system might regulate A. caulinodans nif gene expression ex planta, while the Fnr system might similarly regulate in planta. As nifA upstream-activating elements, we have identified: (i) a gpNifA binding site allowing autogenous nifA regulation, (ii) an Ntr-dependent transcription start, presumably the target of gpNifA activation, and (iii) an "anaerobox" tetradecameric nucleotide sequence that is precisely conserved among O2 regulated enteric bacterial genes controlled by the gpFnr transcriptional activator. Because it is precisely positioned upstream of enteric bacterial transcriptional starts, the "anaerobox" sequence may constitute the gpFnr DNA binding site. If so, then a second, Ntr-independent nifA transcription start may exist. We have also deduced the A. caulinodans nifA open reading frame and have compared the gene product (gpNifA) with those of other N2-fixing organisms. These proteins exhibit strongly conserved motifs: (i) sites conserved among ATP-binding proteins, (ii) an interdomain linker region, and (iii) a C-terminal alpha-helix-turn-alpha-helix DNA binding site.

During isovolumic contraction, there is a calculabe compression of the blood within the ventricle. Energy is expended by the ventricle during isovolumic contraction, and some of it is transferred to the blood in the form of elastic compression. The rate of energy transfer (power) and acceleration of energy transfer (rate of change of power) during isovolumic contraction were calculated based upon considerations of the energy of compression. In anaesthetized dogs, the isovolumic energy of compression was 42 plus or minus 6 (mean plus or minus SE) dyn cm; peak isovolumic power was 1,400 plus or minus 300 dyn cm sec-1; and peak rate of change of power was 56,000 plus or minus 15,000 dyn cm sec-2. During states of augmented contractility induced by isoproterenol, the peak acceleration of energy expeniditure (peak rate of change of power) increased to 126,000 plus or minus 33,000 dyn cm sec-2 (p smaller than 0.001). Conversely, with a reduction of contractility induced by propranolol, the peak isovolumic rate of change of power decreased to 30,000 plus or minus 5,700 dyn cm sec-2 (p smaller than 0.001). The peak rate of change of power was unaffected by changes of the afterload. A trend, however, suggests that it may be affected by preload. The derivations of the isovolumic energy of compression, power, and rate of change of power are based upon firm principles of fluid dynamics. No assumptions related to ventricular geometry, synergy of contraction, or characteristics of muscle fibers are implied. Because of its physiological meaning and the theoretical validity of its derivation, an expression such as the isovolumic peak rate of change of power, when utilized as an index of ventricular performance, would appear to be of value.