Nasal nerve ablation, nasal swell body and inferior turbinate reduction for nasal obstruction and congestion relief.

OBJECTIVE: Nasal obstruction and congestion can occur because of turbinate and septal variations with or without rhinitis. A combined treatment for nasal obstruction and congestion was examined retrospectively in cases where the nasal swell body was addressed with inferior turbinectomy, with or without posterior nasal nerve ablation. METHODS: A 940 nm laser was utilised for contact (nasal swell body, septum and inferior turbinate) and non-contact (posterior nasal nerve) ablation. Total Nasal Symptoms Score, visual analogue scale pain score, complications and procedure location (office vs operating theatre) were recorded. RESULTS: All 242 patients underwent nasal swell body reduction with inferior turbinate reduction, and 150 had posterior nasal nerve ablation also. No laser complications were observed. An 80 per cent reduction in medication usage was noted. Total Nasal Symptoms Score decreased by 73 per cent; rhinorrhoea and congestion scores decreased by 54 per cent and 81 per cent respectively. Crusting, epistaxis and infections were minimal, and resolved within two weeks. CONCLUSION: Nasal swell body with inferior turbinate reduction, with or without posterior nasal nerve ablation, is a new method of treating nasal obstruction and congestion. Laser posterior nasal nerve ablation can be utilised as a complementary tool to deliver anatomical obstruction relief.

Evaluating institutional fit for the conservation of threatened species.

Recovery and conservation of threatened species require adequate institutional responses. We tested an approach to systematically identify and measure how an institutional framework acknowledges threats and required responses for the recovery of endangered species. We measured institutional functional fit with a drivers-pressure-state-impacts-response (DPSIR) model integrated with a quantitative text mining method and qualitative analysis of statutory instruments to examine regulatory responses that support the recovery of 2 endangered species native to Australia, the bridled nailtail wallaby (Onychogalea fraenata) and the Eastern Bristlebird (Dasyornis brachypterus). The key components of the DPSIR model were present in the institutional framework at statutory and operational levels, but some institutional gaps remained in the protection and recovery of the Eastern Bristlebird, including feral predator control, weed control, and grazing management in some locations. However, regulatory frameworks varied in their geographic scope and the application and implementation of many instruments remained optional. Quantitative text mining can be used to quickly navigate a large volume of regulatory documents, but challenges remain in selection of terms, queries of co-occurrence, and interpretation of word frequency counts. To inform policy, we recommend that quantitative assessments of institutional fit be complemented with qualitative analysis and interpreted in light of the sociopolitical and institutional context.

La recuperación y la conservación de las especies amenazadas requieren de respuestas institucionales adecuadas. Evaluamos una estrategia para identificar y medir sistemáticamente cómo un marco de trabajo reconoce las amenazas y las respuestas requeridas para la recuperación de las especies en peligro. Medimos la aptitud funcional institucional mediante un modelo de fuerzas motrices-presión-estado-impacto-respuesta (DPSIR) integrado con un método cuantitativo de extracción de textos y un análisis cualitativo de los instrumentos legales para examinar las respuestas regulatorias que apoyan a la recuperación de dos especies en peligro nativas de Australia: Onychogalea fraenata y Dasyornis brachypterus. Los componentes clave del modelo DPSIR estuvieron presentes en el marco de trabajo institucional a niveles legales y operativos, pero algunos vacíos institucionales permanecieron en la protección y recuperación de D. brachypterus, incluyendo el control de depredadores ferales, el control de malezas y el manejo del pastoreo en algunas localidades. Sin embargo, los marcos de trabajo regulatorios variaron en cuanto a su enfoque geográfico y la aplicación e implementación de muchos de los instrumentos siguieron siendo opcionales. La extracción cuantitativa de textos puede usarse para navegar rápidamente un gran volumen de documentación regulatoria, pero todavía existen obstáculos en la selección de términos, consultas sobre la coocurrencia e interpretación de los conteos de frecuencia de palabras. Para orientar a las políticas recomendamos que las evaluaciones cuantitativas de la aptitud institucional estén complementadas con análisis cuantitativos e interpretadas a la luz del contexto institucional y sociopolítico.

Key considerations and challenges in the application of social-network research for environmental decision making.

Attempts to better understand the social context in which conservation and environmental decisions are made has led to increased interest in human social networks. To improve the use of social-network analysis in conservation, we reviewed recent studies in the literature in which such methods were applied. In our review, we looked for problems in research design and analysis that limit the utility of network analysis. Nineteen of 55 articles published from January 2016 to June 2019 exhibited at least 1 of the following problems: application of analytical methods inadequate or sensitive to incomplete network data; application of statistical approaches that ignore dependency in the network; or lack of connection between the theoretical base, research question, and choice of analytical techniques. By drawing attention to these specific areas of concern and highlighting research frontiers and challenges, including causality, network dynamics, and new approaches, we responded to calls for increasing the rigorous application of social science in conservation.

Consideraciones y Retos Importantes en la Aplicación de la Investigación por medio de Redes Sociales para la Toma de Decisiones Ambientales Resumen Los intentos por tener un mejor entendimiento del contexto social en el que se toman las decisiones ambientales y de conservación han derivado en un incremento en el interés por las redes sociales humanas. Para mejorar el uso del análisis de redes sociales en la conservación, buscamos en la literatura los estudios recientes que hayan aplicado dichos métodos y los sometimos a una revisión. En esta revisión, examinamos los problemas en el diseño de la investigación y del análisis que limitan la utilidad del análisis de redes. Diecinueve de los 55 artículos publicados entre enero 2016 y junio 2019 exhibieron al menos uno de los siguientes problemas: aplicación de métodos analíticos inadecuados o sensibles a la información incompleta sobre las redes; aplicación de estrategias estadísticas que ignoran la dependencia en la red; o falta de conexión entre la base teórica, la pregunta de investigación y la selección de técnica analítica. Al llamar la atención hacia estas áreas específicas de interés y resaltar las fronteras y retos de la investigación, incluyendo la causalidad, las dinámicas de redes y las estrategias nuevas, respondimos a la necesidad de incrementar la aplicación rigurosa de las ciencias sociales en la conservación.

Factoring attitudes towards armed conflict risk into selection of protected areas for conservation.

The high incidence of armed conflicts in biodiverse regions poses significant challenges in achieving international conservation targets. Because attitudes towards risk vary, we assessed different strategies for protected area planning that reflected alternative attitudes towards the risk of armed conflicts. We find that ignoring conflict risk will deliver the lowest return on investment. Opting to completely avoid conflict-prone areas offers limited improvements and could lead to species receiving no protection. Accounting for conflict by protecting additional areas to offset the impacts of armed conflicts would not only increase the return on investment (an effect that is enhanced when high-risk areas are excluded) but also increase upfront conservation costs. Our results also demonstrate that fine-scale estimations of conflict risk could enhance the cost-effectiveness of investments. We conclude that achieving biodiversity targets in volatile regions will require greater initial investment and benefit from fine-resolution estimates of conflict risk.

Seed Storage Globulins: Origin and Evolution of Primary and Higher Order Structures.

Legumin and vicilin are two-domain seed storage globulins similar in primary and higher order structures of their domains to single-domain plant germins as well as to the domains of two-domain and single-domain bacterial oxalate decarboxylases. Independent evolutionary pathways have been shown for the descent of the storage globulins and germins from two-domain and single-domain bacterial oxalate decarboxylases, respectively. As compared to vicilins, the primary and tertiary structures of legumins were found to most closely reflect the ancient features characteristic of a common precursor of storage globulins. During the evolution of the storage globulins, a mechanism specifically controlling their degradation has been formed. We found that limited proteolysis of soybean legumin and kidney bean vicilin in germinating seeds and in vitro leads to their regular changes, which initiate an extensive cleavage of storage globulin molecules by the one-by-one mechanism. As also shown, limited proteolysis of soybean legumin loosens the intersubunit interactions in its oligomeric molecule. Based on these data, we hypothesize that the deep one-by-one degradation of soybean legumin is triggered by its dissociation, which bares peptide bonds potentially susceptible to proteolytic attack but are masked in the oligomer.

Quantitative dose-response curves from subcellular lipid multilayer microarrays.

The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate.

Space and time in the nucleus: developmental control of replication timing and chromosome architecture.

All eukaryotic cells replicate segments of their genomes in a defined temporal sequence. In multicellular organisms, at least half of the genome is subject to changes in this temporal sequence during development. We now know that this temporal sequence and its developmentally regulated changes are conserved across distantly related species, suggesting that it either represents or reflects something biologically important. However, both the mechanism and the significance of this program remain unknown. We recently demonstrated a remarkably strong genome-wide correlation between replication timing and chromatin interaction maps, stronger than any other chromosomal property analyzed to date, indicating that sequences localized close to one another replicate at similar times. This provides molecular confirmation of long-standing cytogenetic evidence for spatial compartmentalization of early- and late-replicating DNA and supports our earlier model that replication timing is reestablished in each G(1) phase, coincident with the anchorage of chromosomal segments at specific locations within the nucleus (timing decision point [TDP]). Here, we review the evidence linking the replication program to the three-dimensional architecture of chromatin in the nucleus and discuss what such a link might mean for the mechanism and significance of a developmentally regulated replication program.

Conserving biodiversity in production landscapes.

Alternative land uses make different contributions to the conservation of biodiversity and have different implementation and management costs. Conservation planning analyses to date have generally assumed that land is either protected or unprotected, and that the unprotected portion does not contribute to conservation goals. We develop and apply a new planning approach that explicitly accounts for the contribution of a diverse range of land uses to achieving conservation goals. Using East Kalimantan (Indonesian Borneo) as a case study, we prioritize investments in alternative conservation strategies and account for the relative contribution of land uses ranging from production forest to well-managed protected areas. We employ data on the distribution of mammals and assign species-specific conservation targets to achieve equitable protection by accounting for life history characteristics and home range sizes. The relative sensitivity of each species to forest degradation determines the contribution of each land use to achieving targets. We compare the cost effectiveness of our approach to a plan that considers only the contribution of protected areas to biodiversity conservation, and to a plan that assumes that the cost of conservation is represented by only the opportunity costs of conservation to the timber industry. Our preliminary results will require further development and substantial stakeholder engagement prior to implementation; nonetheless we reveal that, by accounting for the contribution of unprotected land, we can obtain more refined estimates of the costs of conservation. Using traditional planning approaches would overestimate the cost of achieving the conservation targets by an order of magnitude. Our approach reveals not only where to invest, but which strategies to invest in, in order to effectively and efficiently conserve biodiversity.

Major conservation policy issues for biodiversity in Oceania.

Oceania is a diverse region encompassing Australia, Melanesia, Micronesia, New Zealand, and Polynesia, and it contains six of the world's 39 hotspots of diversity. It has a poor record for extinctions, particularly for birds on islands and mammals. Major causes include habitat loss and degradation, invasive species, and overexploitation. We identified six major threatening processes (habitat loss and degradation, invasive species, climate change, overexploitation, pollution, and disease) based on a comprehensive review of the literature and for each developed a set of conservation policies. Many policies reflect the urgent need to deal with the effects of burgeoning human populations (expected to increase significantly in the region) on biodiversity. There is considerable difference in resources for conservation, including people and available scientific information, which are heavily biased toward more developed countries in Oceania. Most scientific publications analyzed for four threats (habitat loss, invasive species, overexploitation, and pollution) are from developed countries: 88.6% of Web of Science publications were from Australia (53.7%), New Zealand (24.3%), and Hawaiian Islands (10.5%). Many island states have limited resources or expertise. Even countries that do (e.g., Australia, New Zealand) have ongoing and emerging significant challenges, particularly with the interactive effects of climate change. Oceania will require the implementation of effective policies for conservation if the region's poor record on extinctions is not to continue.

Promoting health care safety through training high reliability teams.

Many organizations have been using teams as a means of achieving organizational outcomes (such as productivity and safety). Research has indicated that teams, especially those operating in complex environments, are not always effective. There is a subset of organizations in which teams operate that are able to balance effectiveness and safety despite the complexities of the environment (for example, aviation, nuclear power). These high reliability organizations (HROs) have begun to be examined as a model for those in other complex domains, such as health care, that strive to reach a status of high reliability. In this paper we analyse the components leading to the effectiveness of HROs by examining the teams that comprise them. We use a systems perspective to uncover the behavioral markers by which high reliability teams (HRTs) are able to uphold the values of their parent organizations, thereby promoting safety. Using these markers, we offer guidelines and developmental strategies that will help the healthcare community to shift more quickly to high reliability status by not focusing solely on the organizational level.

Professionals' awareness of operational antibiotic prescribing controls in UK NHS hospitals.

In recent years, there have been increasing recommendations for multidisciplinary collaboration between clinical pharmacists and medical microbiologists in an attempt to control the quality (and quantity) of antibiotic prescribing. A questionnaire addressing the utilization of antibiotic prescribing controls was sent to the chief pharmacist and medical microbiologist in UK NHS hospitals. Responses were received from both the chief pharmacist and the medical microbiologist employed in the same hospital from 83 hospitals (a 30% response rate from two independent studies). A high level of disagreement and poor awareness was identified between the interprofessional staff groups regarding the existence of antibiotic formulary (with disagreement between the two groups, or not known by one or both respondents, in 46% of the paired hospitals, N = 38) and guideline documents (13%, N = 11), performance of antibiotic prescribing audits (40%, N = 33), and whether pharmacists (52%, N = 43) and medical microbiologists (77%, N = 64) monitored physician compliance with antibiotic prescribing control documents. This study has identified poor knowledge of the existence of basic antibiotic prescribing control mechanisms and the role of professional colleagues. It is suggested that there is some way to go before 'Agenda for Change' principles of flexible and collaborative roles are met.

Documentation of antibiotic prescribing controls in UK NHS hospitals.

OBJECTIVES: To identify the types, prevalence and nature of antibiotic prescribing control documents within NHS hospitals in the UK. METHODS: A self-completion postal questionnaire was sent to each Chief Pharmacist at 465 NHS hospitals in 2001/2002. This contained questions covering hospital demographics, and hospital antibiotic prescribing control documentation, including format, dissemination, approval and review processes. RESULTS: In total, 253 (54%) completed questionnaires were returned. Of these, 168 respondents' hospitals had an antibiotic formulary, 107 had a policy for antibiotic prescribing and 216 had guidelines on antibiotic use. All three types of antibiotic prescribing documents were used by 82 hospitals but 18 did not have any documents; 44% of formularies, 45% of policies and 35% of guidelines were available electronically. The Drug and Therapeutics Committee was the most frequently cited body for document approval and approximately one-third of documents had been approved during the current year of the questionnaire. Only about one-half of responding hospitals had an annual review of documents. CONCLUSIONS: Despite publication of high-profile national guidance in response to growing concerns regarding antimicrobial resistance, there has been little increase in the use of antibiotic prescribing control documents in NHS hospitals over the past decade. It is clear that appropriate controls for antibiotic prescribing are not yet universally applied in the UK and recommendations for action have been proposed.

Adverse drug reaction teaching in UK undergraduate medical and pharmacy programmes.

OBJECTIVES: To assess the extent of teaching about the Committee on Safety of Medicine's Yellow Card scheme and adverse drug reactions within UK Schools of Medicine and Pharmacy. METHODS: A self-completed questionnaire sent to all heads of undergraduate schools of medicine and pharmacy within the UK. RESULTS: The majority of undergraduate syllabi feature the Yellow Card Scheme. Knowledge of the Yellow Card Scheme was assessed in 79% of pharmacy programmes and 57% of medical schools. Specialist speakers on the Yellow Card Scheme were infrequently used. Fewer than half of respondents provided students with a guide to reporting ADRs (43% pharmacy and 43% medical). There is some disagreement about the value of supplying students with printed material about the Yellow Card Scheme. Half of medical Schools did not think that supplying 'Current Problems In Pharmacovigilance' would be useful. CONCLUSIONS: It was found that in both medicine and pharmacy, courses differed substantially in teaching about the Yellow Card Scheme and adverse drug reactions (ADRs). There is scope for increased involvement of the Medicines and Healthcare products Regulatory Agency in undergraduate education, in line with recommendations from the National Audit Office.

Evidence that the transmembrane domain proximal region of the human T-cell leukemia virus type 1 fusion glycoprotein gp21 has distinct roles in the prefusion and fusion-activated states.

To investigate the structural context of the fusion peptide region in human T-cell leukemia virus type 1 gp21, maltose-binding protein (MBP) was used as an N-terminal solubilization partner for the entire gp21 ectodomain (residues 313-445) and C-terminally truncated ectodomain fragments. The bacterial expression of the MBP/gp21 chimeras resulted in soluble trimers containing intramonomer disulfide bonds. Detergents blocked the proteolytic cleavage of fusion peptide residues in the MBP/gp21-(313-425) chimera, indicating that the fusion peptide is available for interaction with detergent despite the presence of an N-terminal MBP domain. Limited proteolysis experiments indicated that the transmembrane domain proximal sequence Thr(425)-Ala(439) protects fusion peptide residues from chymotrypsin. MBP/gp21 chimera stability therefore depends on a functional interaction between N-terminal and transmembrane domain proximal regions in a gp21 helical hairpin structure. In addition, thermal aggregation experiments indicated that the Thr(425)-Ser(436) sequence confers stability to the fusion peptide-containing MBP/gp21 chimeras. The functional role of the transmembrane domain proximal sequence was assessed by alanine-scanning mutagenesis of the full-length envelope glycoprotein, with 11 of 12 single alanine substitutions resulting in 1.5- to 4.5-fold enhancements in cell-cell fusion activity. By contrast, single alanine substitutions in MBP/gp21 did not significantly alter chimera stability, indicating that multiple residues within the transmembrane domain proximal region and the fusion peptide and adjacent glycine-rich segment contribute to stability, thereby mitigating the potential effects of the substitutions. The fusion-enhancing effects of the substitutions are therefore likely to be caused by alteration of the prefusion complex. Our observations suggest that the function of the transmembrane domain proximal sequence in the prefusion envelope glycoprotein is distinct from its role in stabilizing the fusion peptide region in the fusion-activated helical hairpin conformation of gp21.

Functional analysis of the disulfide-bonded loop/chain reversal region of human immunodeficiency virus type 1 gp41 reveals a critical role in gp120-gp41 association.

Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the surface-exposed envelope protein (SU) gp120, which binds to cellular CD4 and chemokine receptors, triggering the membrane fusion activity of the transmembrane (TM) protein gp41. The core of gp41 comprises an N-terminal triple-stranded coiled coil and an antiparallel C-terminal helical segment which is packed against the exterior of the coiled coil and is thought to correspond to a fusion-activated conformation. The available gp41 crystal structures lack the conserved disulfide-bonded loop region which, in human T-lymphotropic virus type 1 (HTLV-1) and murine leukemia virus TM proteins, mediates a chain reversal, connecting the antiparallel N- and C-terminal regions. Mutations in the HTLV-1 TM protein gp21 disulfide-bonded loop/chain reversal region adversely affected fusion activity without abolishing SU-TM association (A. L. Maerz, R. J. Center, B. E. Kemp, B. Kobe, and P. Poumbourios, J. Virol. 74:6614-6621, 2000). We now report that in contrast to our findings with HTLV-1, conservative substitutions in the HIV-1 gp41 disulfide-bonded loop/chain reversal region abolished association with gp120. While the mutations affecting gp120-gp41 association also affected cell-cell fusion activity, HIV-1 glycoprotein maturation appeared normal. The mutant glycoproteins were processed, expressed at the cell surface, and efficiently immunoprecipitated by conformation-dependent monoclonal antibodies. The gp120 association site includes aromatic and hydrophobic residues on either side of the gp41 disulfide-bonded loop and a basic residue within the loop. The HIV-1 gp41 disulfide-bonded loop/chain reversal region is a critical gp120 contact site; therefore, it is also likely to play a central role in fusion activation by linking CD4 plus chemokine receptor-induced conformational changes in gp120 to gp41 fusogenicity. These gp120 contact residues are present in diverse primate lentiviruses, suggesting conservation of function.

Protease C2, a cysteine endopeptidase involved in the continuing mobilization of soybean beta-conglycinin seed proteins.

The protease that degrades the beta subunit of the soybean (Glycine max (L.) Merrill) storage protein beta-conglycinin was purified from the cotyledons of seedlings grown for 12 days. The enzyme was named protease C2 because it is the second enzyme to cleave the beta-conglycinin storage protein, the first (protease C1) being one that degrades only the alpha' and alpha subunits of the storage protein to products similar in size and sequence to the remaining intact beta subunit. Protease C2 activity is not evident in vivo until 4 days after imbibition of the seed. The 31 kDa enzyme is a cysteine protease with a pH optimum with beta-conglycinin as substrate of 5.5. The action of protease C2 on native beta-conglycinin produces a set of large fragments (52-46 kDa in size) and small fragments (29-25 kDa). This is consistent with cleavage of all beta-conglycinin subunits at the region linking their N- and C-domains. Protease C2 also cleaves phaseolin, the Phaseolus vulgaris vicilin homologous to beta-conglycinin, to fragments in the 25-28 kDa range. N-Terminal sequences of isolated beta-conglycinin and phaseolin products show that protease C2 cleaves at a bond within a very mobile surface loop connecting the two compact structural domains of each subunit. The protease C2 cleavage specificity appears to be dictated by the substrate's three-dimensional structure rather than a specificity for a particular amino acid or sequence.

The relationship between abdominal aortic aneurysm distensibility and serum markers of elastin and collagen metabolism.

BACKGROUND: abdominal aortic aneurysm (AAA) distensibility may be an independent predictor of growth and rupture, possibly because it reflects changes in aortic wall structure and composition. AIM: to determine whether AAA distensibility is related to circulating markers of elastin and collagen metabolism. METHODS: sixty-two male patients of median age (IQR) 68 (65-72) years with asymptomatic AAA of median (IQR) diameter 42 (37-45) mm were prospectively studied. Pressure-strain elastic modulus (Ep) and stiffness (beta) were measured using an ultrasonic echo-tracker (Diamove). Serum elastin peptides (SEP), plasma elastin-alpha1-antitrypsin complex (E-AT), procollagen III-N-terminal propeptide (PIIINP) were measured by enzyme-linked immunoassay. RESULTS: age and smoking adjusted Ep and beta were significantly inversely related to SEP (r=-0.33 and r=-0.31 respectively, both p<0.02) and E-AT (r=-0.27 and r=-0.27 respectively, both p<0.05) both of which indicate elastolysis. By contrast, there was a significant positive correlation between PIIINP, indicative of increased collagen turn-over, and both Ep and beta (both r=0.45, p<0.01 unadjusted correlations). CONCLUSION: increased elastolysis is associated with increased AAA wall distensibility; whereas increased collagen turn-over is associated with reduced distensibility.

Team training in the skies: does crew resource management (CRM) training work?

The aviation community has invested great amounts of money and effort into crew resource management (CRM) training. Using D. L. Kirkpatrick's (1976) framework for evaluating training, we reviewed 58 published accounts of CRM training to determine its effectiveness within aviation. Results indicated that CRM training generally produced positive reactions, enhanced learning, and promoted desired behavioral changes. However, we cannot ascertain whether CRM has an effect on an organization's bottom line (i.e., safety). We discuss the state of the literature with regard to evaluation of CRM training programs and, as a result, call for the need to conduct systematic, multilevel evaluation efforts that will show the true effectiveness of CRM training. As many evaluations do not collect data across levels (as suggested by D. L. Kirkpatrick, 1976, and by G. M. Alliger, S. I. Tannenbaum, W. Bennett, Jr., & H. Traver, 1997), the impact of CRM cannot be truly determined; thus more and better evaluations are needed and should be demanded.

Tolerability of large-dose intravenous levobupivacaine in sheep.

UNLABELLED: In preclinical pharmacological studies of levobupivacaine (S-bupivacaine), we determined its tolerability, cardiovascular actions, and pharmacokinetics, and we estimated its margin of safety compared with bupivacaine in conscious sheep. Levobupivacaine HCl. H(2)O was infused IV for 3 min into 10 previously instrumented ewes (approximately 50 kg). On subsequent days, the doses were increased by 50 mg from 200 or 250 mg until fatality occurred. All doses produced convulsions, QRS widening, and cardiac arrhythmias. With incremental doses, 4 of 4 animals survived 200 mg, 7 of 10 survived 250 mg, 3 of 7 survived 300 mg, but 0 of 3 survived 350 mg. Death resulted from sudden onset ventricular fibrillation (n = 3, within 2-3 min), electromechanical dissociation-pump failure (n = 5, within 4-5 min), or ventricular tachycardia-induced cardiac insufficiency (n = 2, >10 min). The estimated fatal dose (mean +/- SD) was 277 +/- 51 mg for levobupivacaine (compared with 156 +/- 31 mg found previously for bupivacaine). Pharmacokinetic analysis indicated initial and total distribution volumes = 4.5 (+/-1.6) and 97 (+/-22) L, total clearance = 1.7 (+/-0.4) L/min, and slow half life = 70 (+/-29) min; these values did not differ from those found previously with smaller doses. Heart and brain tissue levobupivacaine concentrations were approximately 3 times those in arterial blood. The doses of levobupivacaine survived were larger than found previously for bupivacaine, indicating its greater margin of safety. IMPLICATIONS: Levobupivacaine produced fatal cardiac toxicity at doses significantly greater than those found in previous studies with bupivacaine. As the two drugs have similar potency for producing clinical nerve blocks, the data imply that levobupivacaine should provide a safer alternative to bupivacaine in practice.

Dietary sulfur amino acid requirement of juvenile yellow perch fed the maximum cystine replacement value for methionine.

We conducted three separate experiments designed to determine the dietary methionine requirement, ability of cyst(e)ine to spare methionine, and the total sulfur amino acid requirement (TSAA) of juvenile yellow perch when fed the maximal amount of cyst(e)ine. The purified basal diet used in each experiment contained 33.6 g of crude protein/100 g diet and 12.0 g of lipid/100 g diet. In the first experiment,;>L-methionine was added to eight diets providing methionine concentrations ranging from 0.37 to 1.77 g/100 g diet in gradations of 0.2 g/100 g diet. Diets were fed for 12 wk to juvenile yellow perch initially weighing 4.7 g/fish. Broken-line analyses of weight gain and feed efficiency data indicated that the dietary methionine requirement was 1.0 g/100 g diet (3.1 g TSAA/100 g dietary protein) and 1.1 g/100 g diet (3.4 g TSAA/100 g dietary protein), respectively. In the second experiment, various ratios of L-cyst(e)ine and L-methionine were added to the basal diet and fed for 12 wk to determine the cyst(e)ine replacement value of yellow perch initially weighing 19.3 g/fish. Weight gain and feed efficiency (FE) data indicated that cyst(e)ine spared up to 51% of the methionine requirement. In the final experiment, graded levels of cyst(e)ine plus methionine in a ratio of 51:49 were added to the basal diet in gradations of 0.1 g/100 g diet (0.5 to 1.2 g TSAA/100 g diet) to determine the dietary total sulfur amino acid requirement. Diets were fed to satiation for 10 wk to fish initially weighing 8. 1 g. Broken-line analyses of weight gain, feed intake and FE data indicated that the dietary TSAA requirement was 0.85, 0.87 and 1.0 g of TSAA/100 g diet (2.5 to 3.0 g of TSAA/100 g of dietary protein), respectively. The majority of dietary TSAA requirements of fish are in the range of 2 to 4 g/100 g of dietary protein and are generally similar to those of both birds and swine, but lower than estimates for rodents.