Understanding the impact of barriers to onward migration; a novel approach using translocated fish.

River catchments worldwide are heavily fragmented by anthropogenic barriers, reducing their longitudinal connectivity and contributing to the decline of migratory fish populations. Direct impacts of individual barriers on migratory fish are well-established, but barrier impacts on onward migration are poorly understood, despite their relevance to evidence-based, catchment-scale, management of threatened species. This study investigated the upstream spawning migration of 352 acoustic tagged river lamprey (Lampetra fluviatilis), translocated upstream of two key barriers (R2: n = 60 & 59; R3: n = 59 & 52) compared to a control group (R1: n = 61 & 59), across two contrasting (dry and wet, n = 180 and 172) years in the River Yorkshire Ouse, England, to reveal the impact of barriers on the onward migration of upstream migrating fish. Release further upstream increased the degree of catchment penetration, with median distance upstream of R1 56.1% and 68.6% greater for lamprey released at R2 and R3 respectively. Median delays at the two downstream-most main river barriers by the control group were 23.8 and 5.4 days (2018/19) and 9.3 and 11.4 days (2019/20). However, impacts of delay were only observed on the time to reach spawning habitat, time to reach final assumed spawning location and speed of movement in one upper catchment tributary during 2019/20 whilst they were only observed on time to reach spawning habitat during 2018/19 and on assumed spawning location distance during 2019/20 in the other. Ultimately, limited impacts of delay at barriers on onward fish migration post-passage were observed but median catchment penetration was increased with consecutive release upstream. This study demonstrated the importance of a true understanding of barrier impacts to inform catchment-wide planning, evidence vital for management worldwide. Although the findings of this study do support the use of trap and transport as a measure to remediate barrier impacts on migration, fish passage engineering improvements or barrier removal, at structures shown to be the most inhibiting to fish migration should be considered the best and most sustainable option to improve barrier passage.

Overcoming the dichotomy of implementing societal flood risk management while conserving instream fish habitat - A long-term study from a highly modified urban river.

Flood Risk Management (FRM) is often essential to reduce the risk of flooding to properties and infrastructure in urban landscapes, but typically degrades the habitats required by many aquatic animals for foraging, refuge and reproduction. This conflict between flood risk management and biodiversity is driven by conflicting directives, such as the EU Floods and Water Framework Directives, and has led to a requirement for synergistic solutions for FRM that integrate river restoration actions. Unfortunately, ecological monitoring and appraisal of combined FRM and river restoration works is inadequate. This paper uses a case study from the River Don in Northern England to evaluate the effects of the FRM and subsequent river restoration works on instream habitat and the associated fish assemblage over an 8-year period. Flood risk management created a homogeneous channel but did not negatively affect fish species composition or densities, specifically brown trout. Densities of adult brown trout were comparable pre and post-FRM, while densities of juvenile bullhead and brown trout increased dramatically post FRM. River restoration works created a heterogeneous channel but did not significantly improve species composition or brown trout density. Species composition post-river restoration works returned to that similar to pre-FRM over a short-term period, but with improved numbers of juvenile bullhead. Although habitat complexity increased after river restoration works, long-term changes in species composition and densities were marginal, probably because the river reset habitat complexity within the time framework of the study.

Differences in Abundances of Total Vibrio spp., V. vulnificus, and V. parahaemolyticus in Clams and Oysters in North Carolina.

Filter feeding shellfish can concentrate pathogenic bacteria, including Vibrio vulnificus and Vibrio parahaemolyticus, as much as 100-fold from the overlying water. These shellfish, especially clams and oysters, are often consumed raw, providing a route of entry for concentrated doses of pathogenic bacteria into the human body. The numbers of foodborne infections with these microbes are increasing, and a better understanding of the conditions that might trigger elevated concentrations of these bacteria in seafood is needed. In addition, if bacterial concentrations in water are correlated with those in shellfish, then sampling regimens could be simplified, as water samples can be more rapidly and easily obtained. After sampling of oysters and clams, either simultaneously or separately, for over 2 years, it was concluded that while Vibrio concentrations in oysters and water were related, this was not the case for levels in clams and water. When clams and oysters were collected simultaneously from the same site, the clams were found to have lower Vibrio levels than the oysters. Furthermore, the environmental parameters that were correlated with levels of Vibrio spp. in oysters and water were found to be quite different from those that were correlated with levels of Vibrio spp. in clams. IMPORTANCE: This study shows that clams are a potential source of infection in North Carolina, especially for V. parahaemolyticus These findings also highlight the need for clam-specific environmental research to develop accurate Vibrio abundance models and to broaden the ecological understanding of clam-Vibrio interactions. This is especially relevant as foodborne Vibrio infections from clams are being reported.

Observation of Quasichanneling Oscillations.

We report on the first experimental observations of quasichanneling oscillations, recently seen in simulations and described theoretically. Although above-barrier particles penetrating a single crystal are generally seen as behaving almost as in an amorphous substance, distinct oscillation peaks nevertheless appear for particles in that category. The quasichanneling oscillations were observed at SLAC National Accelerator Laboratory by aiming 20.35 GeV positrons and electrons at a thin silicon crystal bent to a radius of R=0.15 m, exploiting the quasimosaic effect. For electrons, two relatively faint quasichanneling peaks were observed, while for positrons, seven quasichanneling peaks were clearly identified.

Vibrio parahaemolyticus and Vibrio vulnificus in South America: water, seafood and human infections.

The bacterial species, Vibrio parahaemolyticus and Vibrio vulnificus, are ubiquitous in estuaries and coastal waters throughout the world, but they also happen to be important human pathogens. They are concentrated by filter-feeding shellfish which are often consumed raw or undercooked, providing an important potential route of entry for an infective dose of these bacteria. Vibrio parahaemolyticus can cause abdominal cramping, nausea, diarrhoea, vomiting, chills and fever. Vibrio vulnificus can cause similar gastrointestinal-related symptoms, but can also spread to the bloodstream, resulting in primary septicaemia, and it can also cause disease via wound infections. The objective of this article is to summarize, for the first time, the incidence and importance of V. parahaemolyticus and V. vulnificus in South America, in environmental waters and seafood, especifically molluscan shellfish, as well as human infection cases and outbreaks. It appears that infections from V. parahaemolyticus have been more strongly related to shellfish ingestion and have been more frequently reported on the Pacific coast of South America. Conversely, V. vulnificus has been more frequently acquired by water contact with open wounds and its presence has been more heavily reported along the Atlantic coast of South America, and while documented to cause serious mortality, have been relatively few in number. The impacts of El Nino Southern Oscillation (ENSO) have been observed to cause an increase in V. parahaemolyticus outbreaks on the Pacific coast of South America. The implementation of a regulated monitoring approach, along with the use of faster, more accurate and virulence-specific detection approaches, such as PCR confirmation, should be considered to detect the presence of pathogenic Vibrio strains in environmental and seafood samples for protection of public health. Furthermore, improved clinical surveillance with suspected cases should be implemented. This review highlights the need for more research and monitoring of vibrios in South America, in water, shellfish and clinical samples.

Development of a matrix tool for the prediction of Vibrio species in oysters harvested from North Carolina.

The United States has federal regulations in place to reduce the risk of seafood-related infection caused by the estuarine bacteria Vibrio vulnificus and Vibrio parahaemolyticus. However, data to support the development of regulations have been generated in a very few specific regions of the nation. More regionally specific data are needed to further understand the dynamics of human infection relating to shellfish-harvesting conditions in other areas. In this study, oysters and water were collected from four oyster harvest sites in North Carolina over an 11-month period. Samples were analyzed for the abundances of total Vibrio spp., V. vulnificus, and V. parahaemolyticus; environmental parameters, including salinity, water temperature, wind velocity, and precipitation, were also measured simultaneously. By utilizing these data, preliminary predictive management tools for estimating the abundance of V. vulnificus bacteria in shellfish were developed. This work highlights the need for further research to elucidate the full suite of factors that drive V. parahaemolyticus abundance.

Observation of deflection of a beam of multi-GeV electrons by a thin crystal.

We report on an experiment performing channeling and volume reflection of a high-energy electron beam using a quasimosaic, bent silicon (111) crystal at the End Station A Test Beam at SLAC. The experiment uses beams of 3.35 and 6.3 GeV. In the channeling orientation, deflections of the beam of 400 µrad for both energies with about 22% efficiency are observed, while in the volume-reflection orientation, deflection of the beam by 120 µrad at 3.35 GeV and by 80 µrad at 6.3 GeV is observed with 86%-95% efficiency. Quantitative measurements of the channeling efficiency, surface transmission, and dechanneling length are taken. These are the first quantitative measurements of channeling and volume reflection using a primary beam of multi-GeV electrons.

Comparison of vestipitant with ondansetron for the treatment of breakthrough postoperative nausea and vomiting after failed prophylaxis with ondansetron.

BACKGROUND: Postoperative nausea and vomiting (PONV) is common; ondansetron is often used as prophylaxis or for breakthrough episodes. Vestipitant is a neurokinin 1 (NK-1) receptor antagonist that is effective for prophylaxis, but its efficacy for treating established PONV is unknown. This study was performed to evaluate the efficacy and safety of vestipitant, compared with ondansetron for the treatment of breakthrough PONV in patients who had already received prophylactic ondansetron before surgery. METHODS: A multicentre, randomized, single-blind (sponsor-open), parallel group study. Of 527 surgical patients, 130 (25%) had breakthrough PONV and were equally randomized to one of six i.v. doses of vestipitant (4-36 mg) or ondansetron 4 mg. The primary endpoint was the rate of patients exhibiting complete response, defined as no emesis and no further rescue medication from 10 min after infusion up to 24 h after surgery or hospital discharge. RESULTS: All doses of vestipitant were non-inferior to ondansetron in treating PONV after failed prophylaxis with ondansetron. However, vestipitant was superior to ondansetron in decreasing episodes of postoperative emesis and retching. The complete response rate analysis using Bayesian model averaging indicated that no vestipitant dose was superior to ondansetron. Nausea numerical rating scale scores and the times-to-PONV or discharge were similar between the vestipitant and ondansetron treatment groups. CONCLUSIONS: Although overall efficacy was non-inferior between vestipitant and ondansetron, the rate of emesis was lower with vestipitant. These data suggest that vestipitant may be a useful agent for the management of PONV, similar to other NK-1 antagonists. CLINICAL TRIAL REGISTRATION: NCT01507194.

Microbial water quality before and after the repair of a failing onsite wastewater treatment system adjacent to coastal waters.

AIMS: The objective was to assess the impacts of repairing a failing onsite wastewater treatment system (OWTS, i.e., septic system) as related to coastal microbial water quality. METHODS AND RESULTS: Wastewater, groundwater and surface water were monitored for environmental parameters, faecal indicator bacteria (total coliforms, Escherichia coli, enterococci) and the viral tracer MS2 before and after repairing a failing OWTS. MS2 results using plaque enumeration and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) often agreed, but inhibition limited the qRT-PCR assay sensitivity. Prerepair, MS2 persisted in groundwater and was detected in the nearby creek; postrepair, it was not detected. In groundwater, total coliform concentrations were lower and E. coli was not detected, while enterococci concentrations were similar to prerepair levels. E. coli and enterococci surface water concentrations were elevated both before and after the repair. CONCLUSIONS: Repairing the failing OWTS improved groundwater microbial water quality, although persistence of bacteria in surface water suggests that the OWTS was not the singular faecal contributor to adjacent coastal waters. A suite of tracers is needed to fully assess OWTS performance in treating microbial contaminants and related impacts on receiving waters. Molecular methods like qRT-PCR have potential but require optimization. SIGNIFICANCE AND IMPACT OF STUDY: This is the first before and after study of a failing OWTS and provides guidance on selection of microbial tracers and methods.

A modified thrombin clotting time test as a quality control marker for heparin contamination in obstetric intraoperative cell salvage.

OBJECTIVE: To assess if a modified thrombin clotting time test could be used as a simple quality control (QC) method to screen for unfractionated heparin in the product obtained from obstetric intraoperative cell salvage cases before re-infusion. BACKGROUND: A national QC scheme has recently been piloted to monitor the quality of autologous blood being returned to the patient. Laboratory tests include full blood count and microalbumin. Unfractionated heparin testing should be performed to ensure that there is no gross contamination of heparin in the final product; however, presently, there is no quick cheap test available suitable for heparin detection. MATERIALS AND METHODS: Samples were collected into plain non-anticoagulated tubes and centrifuged at 2500 × g for 5 min. Supernatant was mixed with commercially available coagulated normal plasma and a thrombin clotting time test performed. RESULTS: Calibration runs demonstrated that our system was sensitive up to 0 · 14 IU mL(-1) heparin, linear between 0 · 08 and 0 · 14 IU mL(-1). CONCLUSION: We have shown that the thrombin clotting time test can be modified and used as a cheap and reliable marker for heparin contamination. We have successfully incorporated this modified test into our hospital's obstetric QC scheme.

Tracking microbial transport through four onsite wastewater treatment systems to receiving waters in eastern North Carolina.

AIMS: To examine microbial transport through properly functioning and failing onsite wastewater treatment systems (OWTS) and its implication in surrounding water quality. METHODS AND RESULTS: Water samples were collected from monitoring wells near leach lines of OWTS and nearby ditches and receiving surface waters to analyse for Escherichia coli and enterococci. Tracer studies with Rhodamine WT (RWT) and coliphage MS2 were also carried out to understand the fate and transport of contaminants through each OWTS. Escherichia coli and enterococci concentrations were higher around failing than properly functioning OWTS by as much as 85-fold. A storm event resulting in 9·5 cm of rainfall increased E. coli and enterococci concentrations by averages of 4·1 × 10³ and 7·9 × 10³ MPN per 100 ml, respectively, in wells close to the OWTS. MS2 persisted in the wastewater distribution boxes of the OWTS for several months and was detected in some outer perimeter wells. CONCLUSIONS: Properly functioning OWTS in eastern North Carolina were effective in treating wastewater, whereas the failing OWTS affected the groundwater quality more adversely, especially after a rain storm, but had minor impact on the nearby coastal surface water. SIGNIFICANCE AND IMPACT OF THE STUDY: The study is the first description of the microbial contaminant signature stemming from properly functioning and failing systems under regular use in a high-priority coastal area.

A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.

Idiotypic cross-reactivity between antibodies of different specificities.

Cross-idiotypic specificity has been demonstrated between antibody populations of different specificities using antibodies directed toward human sickle cell hemoglobin (HbS). A site-specific antibody directed toward the beta6-position of HbS, anti-Val, was used to elicit an anti-idiotypic response in rabbits. Using this anti-idiotypic serum, idiotypic cross-reactivity was demonstrated between antibody populations that bind to human adult hemoglobin (HbA). It was demonstrated that in the case of the goat antibodies, these idiotypically cross-reacting antibodies are directed towards the beta6-position of the hemoglobin molecule. However, they differ in their specificity, binding to this site on HbA, whereas anti-Val binds only to HbS. The sheep antibody populations directed toward HbS differ qualitatively from those of the goat. Using rabbit anti-idiotypic serum specific for sheep anti-Val, cross-reactivity could be demonstrated with antibodies directed toward the alpha-chain of the hemoglobin molecule, as well as the beta-chain. There was also a low level of cross-reactivity with antibodies from a goat immunized with HbA.

Evolution of an idiotypic determinant: anti-Val.

An antibody population which reacts only with human sickle cell hemoglobin (HbS) and not with normal human hemoglobin, has been isolated from goat, sheep, and guinea pig antisera. These antibody populations termed anti-Val (Val), isolated from an individual goat (no. 6) and sheep (no. 26) have been used to elicit anti-idiotypic responses in rabbits. These anti-idiotypic sera were used to study the idiotypic cross-reactions between the goat and sheep anti-Val. Strong cross-reactions were present using either Ra anti-goat anti-Val or Ra anti-sheep anti-Val. Guinea pig anti-Val did not cross-react with these anti-idiotypic sera. Binding of HbS to the anti-Val of the goat and sheep could be blocked by the anti-idiotypic sera, but the binding of HbS to the guinea pig anti-Val could not. These data demonstrate idiotypic cross-reactivity between two closely related species.

[Argentinean consensus guidelines on the use of monoclonal antibodies in patients with migraine]. / Consenso sobre el uso de anticuerpos monoclonales en la migraña en Argentina.

INTRODUCTION: Migraine is a very prevalent disorder that is estimated to affect about 15% of adult subjects. Recently, the efficacy and safety of monoclonal antibodies that act on the calcitonin gene-related peptide pathway (MA-CGRP) has been evaluated in migraine. Several groups around the world have developed consensus guidelines about the use of monoclonal antibodies, however, in some regions is difficult to extrapolate the recommendations. AIM: To provide recommendations for the use of MA-CGRP in migraine in Argentina. DEVELOPMENT: A group of neurology experts from Argentina, by using the online surveys methodology as well as face to face meetings developed the intended consensus for the use of MA-CGRP in migraine in Argentina. Recommendations were established based on published evidence and the expert opinion. Recommendations focused on how, when, treatment duration and patients follow up. CONCLUSION: The recommendations of this consensus guidelines attempt to optimize the use of MA-CGRP in migraine in Argentina.

TITLE: Consenso sobre el uso de anticuerpos monoclonales en la migraña en Argentina.Introducción. La migraña es un trastorno muy prevalente que se estima que afecta a alrededor del 15% de los sujetos adultos. Durante los últimos años, se ha evaluado la eficacia y la seguridad de los anticuerpos monoclonales que actúan sobre la vía del péptido relacionado con el gen de la calcitonina (AM-PRGC) en la migraña. Diversos grupos de trabajo internacionales han intentado clarificar y normatizar el uso de estos medicamentos en la migraña. Sin embargo, en muchas ocasiones se extrapolan datos de otras regiones que no contemplan la realidad de cada lugar o son difíciles de implementar. Objetivo. Proveer recomendaciones sobre el uso de AM-PRGC en pacientes con migraña en Argentina. Desarrollo. Un grupo de expertos de Argentina conformado por neurólogos, mediante metodología de ronda de encuestas en la distancia y reuniones presenciales, llevó adelante la elaboración del consenso pretendido para el uso de AM-PRGC en pacientes con migraña en Argentina. Se establecieron las recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el momento de usar los AM-PRGC en la migraña tanto crónica como episódica, la duración, los cuidados y el entorno para hacerlo. Conclusión. Las recomendaciones establecidas en el presente consenso permitirán optimizar el manejo de los AM-PRGC en pacientes con migraña en Argentina.

Admixed human embryos and stem cells: legislative, ethical and scientific advances.

This paper examines the regulatory framework currently governing the creation of animal-human hybrids and chimera embryos in stem cell research, and some of the ethical implications of such research. It discusses the findings of a recent government select committee that considered the topic. It considers the debate around the precise definition of a human embryo, and whether such hybrids therefore fall within the remit of the Human Fertilisation and Embryology Authority. It outlines the advantages of such hybrids, in lessening the need for human egg donors, as well as the moral objections to species boundary violation. It calls for an examination of the scientific benefits of such research to inform debate on the question, and argues for the need to take genuine account of the public's views on this matter.

Turnover of plasma cholesterol in man.

Cholesterol-4-(14)C was injected intravenously into a series of normal men, untreated hyperlipidemic patients, and hyperlipidemic patients being treated with cholestyramine. The specific radioactivity of plasma total cholesterol was measured during the ensuing 10 wk. 16 studies were carried out in 10 subjects. Analysis of the turnover curves of plasma cholesterol revealed that in every study the turnover of plasma cholesterol conformed to a two-pool model. Each turnover curve was analyzed in terms of this model, as expressed by the equation: specific activity = C(A)e(-alphat) + C(B)e(-betat). The parameters which were calculated included the constants C(A), C(B), alpha, and beta; the size of the first pool (M(A)); the rate constants for the total rate of removal of cholesterol from each pool (k(AA) and k(BB)); and the production rate in pool A (PR(A)). In two normal men and five untreated patients the average size of pool A was 25g. The effect of cholestyramine was assessed by comparing the results obtained without therapy with those obtained during therapy in five subjects studied under both conditions. Cholestyramine therapy produced a large increase in PR(A) (from 0.98 to 1.98 g/day) and in the rate of removal of cholesterol from pool A. Cholestyramine did not significantly alter the size of pool A. It is not possible to calculate the size of the total body exchangeable pool of cholesterol from the turnover curve of plasma cholesterol. It is also not possible to calculate the metabolic turnover rate, i.e., the rate of cholesterol degradation and excretion, in the whole body. This parameter can, however, be estimated by assuming that cholesterol is removed from the body only by way of the tissue pools that comprise pool A. Under these conditions the metabolic turnover rate is equal to the production rate in pool A.

The demonstration of alternating contractile state in pulsus alternans.

Pulsus alternans was induced in 11 anesthetized, open-chest dogs by rapid atrial pacing, and the left ventricular filling characteristics and length-tension-velocity relationship of alternating beats were compared. The end-diastolic circumferences (cire) of the strong beats were slightly, but significantly, increased over the weak beats (7.3 > 6.9 cm, P < 0.01), confirming that diastolic filling does alternate in pulsus alternans. This alternation in initial fiber length seemed to result from an alternation in the prior end-systolic length, rather than from an alternation in diastolic filling time or compliance. There was also no difference in end-diastolic tension as measured by an isometric strain gauge suggesting no difference in contractile element relaxation before weak and strong beats. THE CONTRACTILE STATE OF THE STRONG BEATS WAS CONSISTENTLY GREATER THAN THAT OF THE WEAK BEATS WHEN CONTRACTILITY WAS DEFINED IN TERMS OF: (a) V(max) (3.13 > 2.53 circ/sec, P < 0.01); and (b) the velocity of circumferential fiber shortening (0.84 > 0.39 circ/sec, P < 0.001) and developed tension (82.5 > 74 g/cm, P < 0.01) at isolength. The length-tension-velocity relationship of the left ventricle also varied between strong and weak beats when: (a) the maximum velocity of contractile element shortening at least common tension (1.68 > 1.28 circ/sec, P < 0.05); and (b) the velocity of circumferential fiber shortening (0.81 > 0.39 circ/sec, P < 0.001) at maximum developed tension were examined. Analysis of the length-tension-velocity characteristics of sequential beats at the onset of alternans in three dogs suggests that an alternation in contractility initiates alternans, with secondary alternations in ventricular filling. Cross-clamping of the aorta in three other dogs essentially eliminated the alternating changes in end-diastolic length and pressure, while the resultant isovolumic contractions continued to demonstrate clear evidence of pulsus alternans in the ventricular systolic pressure, suggesting the persistance of an alternating contractile state. The evidence suggests that an important mechanism in the production and propagation of pulsus alternans, as produced in the intact canine ventricle by rapid pacing, is a beat-to-beat alternation in contractile state with secondary alternations in ventricular filling.

The effects of colestipol resin and of colestipol plus clofibrate on the turnover of plasma cholesterol in man.

Studies were conducted to determine the effects of colestipol hydrochloride, a new bile acid-sequestrant resin, on some of the parameters of cholesterol turnover and metabolism in man. Three normal volunteers and eight hyperlipidemic patients participated in three sets of cholesterol turnover studies carried out at intervals of approximately 1 yr. The effects of colestipol were assessed by comparing the results obtained before therapy with those obtained on repeat study after several months of resin therapy. Colestipol treatment significantly reduced the serum cholesterol concentration (mean reduction 21%), and produced a large increase in the production rate of cholesterol (mean 86%) and in the turnover rate of cholesterol in pool 1 (mean 46%). The values of the intercompartmental rate constants and of the size of the rapidly exchangeable pool were unchanged with therapy. The turnover studies were carried out for 12-13 wk, and were analyzed according to a two-pool model. Although long-term studies of cholesterol turnover conform to a three-pool, rather than a two-pool model, the present studies probably provide a valid estimate of the effects of therapy on certain parameters, namely the production rate, the size, and the turnover rate of pool 1. Repeated studies in four untreated subjects showed a striking constancy with time for the kinetic parameters for each subject. The production rate was particularly constant from year to year for a given subject, and showed a pooled standard deviation of only 3%. The findings suggest that the total body turnover of cholesterol is under close homeostatic control in an integrated manner. Combined drug therapy with colestipol plus clofibrate further reduced the serum cholesterol level in three of four patients, and reduced the triglyceride level in all four patients. Addition of clofibrate to the treatment program produced only small decreases in the production rate, which were not significantly different from the small decreases seen in two patients who were continued (and restudied) on colestipol alone. The findings do not support the suggestion that clofibrate can block the increased rate of cholesterol synthesis and turnover resulting from bile acid-sequestrant treatment. The effects on serum lipids, however, make the combined drug therapy potentially quite useful.

Parameters of the three-pool model of the turnover of plasma cholesterol in normal and hyperlipidemic humans.

Long-term studies (32-49 wk) of the turnover of plasma cholesterol were conducted in 24 subjects. Eight subjects were normilipidemic, six had hypercholesterolemia, eight had hypercholesterolemia and hypertriglyceridemia, and two had hypertriglyceridemia alone. 10 of the hyperlipidemic patients had a definite familial disorder. In all subjects (except one for whom complete data were not available), the same three-pool model previously described gave the best fit for the data. The parameters of the three-pool model observed in the normal subjects were compared with the model parameters found in the patients with the different kinds of hyperlipidemia. In addition, single and multiple regression analyses were conducted to explore the relationships between the model parameters and various physiological variables, including age, body size, and serum lipid concentrations. Using this approach, significant differences between groups, or correlations with serum lipid levels were seen for several parameters of the three-pool model: the production rate (PR); the size of the rapidly exchanging pool 1 (M1); all estimates of the size of the most slowly equilibrating pool 3 (M3); and the rate constant k21. The PR in normal subjects (1.14 +/- 0.19 g/day, mean +/- SD) was not significantly different from that found in patients with hypercholesterolemia, with or without hypertriglyceridemia. The major determinant of cholesterol PR was overall body size, expressed either as total body weight or as surface area. The correlations between PR and indices of adiposity (percent ideal weight and excess weight), although statistically significant, were much weaker in this nonobese population. After adjustment for body size variation, cholesterol PR was not correlated with the serum cholesterol concentration but was probably (P less than 0.05) correlated with the triglyceride concentration. When the two patients with very high triglyceride concentrations were excluded, however, no correlation was observed between adjusted PR and triglyceride level. It is probable that hypertriglyceridemic patients represent a heterogeneous population, in which the majority do not show increased cholesterol PR. M1 was correlated with all body size variables, but most strongly with excess weight. After adjusting for the effects of body size, M1 was also correlated and triglyceride. Major differences were found in the relationships between the physiological variables and the sizes of pools 2 and 3. M2 was correlated neither with any of the indices of body size or adiposity, nor with the serum levels of either cholesterol or triglyceride. In contrast, all estimates of M3 were correlated with indices of adiposity (but not of overall body size) and with the serum cholesterol concentration. Thus, the amount of cholesterol in slowly equilibrating tissue sites appears to particularly increase with elevations of the serum cholesterol level. The results also confirm previous data that adipose tissue cholesterol is an important part of pool 3.