Understanding the Haemodynamics of Hypertension.

PURPOSE OF REVIEW: This article introduces the haemodynamic principles that underpin the pathophysiology of hypertension and introduces a rational physiological approach to appropriate pharmacologic treatment. RECENT FINDINGS: Outdated understanding of haemodynamics based on previous measurement systems can no longer be applied to our understanding of the circulation. We question the current view of hypertension as defined by a predominantly systolic blood pressure and introduce the concept of vasogenic, cardiogenic and mixed-origin hypertension. We postulate that failure to identify the individual's haemodynamic pattern may lead to the use of inappropriate medication, which in turn may be a major factor in patient non-compliance with therapeutic strategies. A population-based approach to treatment of hypertension may lead to suboptimal functional dynamics in the individual patient. Finally, we question the validity of current guidelines and published evidence relating morbidity and mortality to the future treatment of hypertension. The importance of individual haemodynamic profiles may be pivotal in the understanding, diagnosis and treatment of hypertension if optimal control with minimal adverse effects is to be achieved. Research based on individual haemodynamic patterns is overdue.

A trans-Atlantic examination of haddock Melanogrammus aeglefinus food habits.

The food habits of Melanogrammus aeglefinus were explored and contrasted across multiple north-eastern and north-western Atlantic Ocean ecosystems, using databases that span multiple decades. The results show that among all ecosystems, echinoderms are a consistent part of M. aeglefinus diet, but patterns emerge regarding where and when M. aeglefinus primarily eat fishes v. echinoderms. Melanogrammus aeglefinus does not regularly exhibit the increase in piscivory with ontogeny that other gadoids often show, and in several ecosystems there is a lower occurrence of piscivory. There is an apparent inverse relationship between the consumption of fishes and echinoderms in M. aeglefinus over time, where certain years show high levels of one prey item and low levels of the other. This apparent binary choice can be viewed as part of a gradient of prey options, contingent upon a suite of factors external to M. aeglefinus dynamics. The energetic consequences of this prey choice are discussed, noting that in some instances it may not be a choice at all.

Quantifying alosine prey in the diets of marine piscivores in the Gulf of Maine.

The objectives of this work were to quantify the spatial and temporal distribution of the occurrence of anadromous fishes (alewife Alosa pseudoharengus, blueback herring Alosa aestivalis and American shad Alosa sapidissima) in the stomachs of demersal fishes in coastal waters of the north-west Atlantic Ocean. Results show that anadromous fishes were detectable and quantifiable in the diets of common marine piscivores for every season sampled. Even though anadromous fishes were not the most abundant prey, they accounted for c. 5-10% of the diet by mass for several marine piscivores. Statistical comparisons of these data with fish diet data from a broad-scale survey of the north-west Atlantic Ocean indicate that the frequency of this trophic interaction was significantly higher within spatially and temporally focused sampling areas of this study than in the broad-scale survey. Odds ratios of anadromous predation were as much as 460 times higher in the targeted sampling as compared with the broad-scale sampling. Analyses indicate that anadromous prey consumption was more concentrated in the near-coastal waters compared with consumption of a similar, but more widely distributed species, the Atlantic herring Clupea harengus. In the context of ecosystem-based fisheries management, the results suggest that even low-frequency feeding events may be locally important, and should be incorporated into ecosystem models.

Non-invasive method for rapid bedside estimation of inotropy: theory and preliminary clinical validation.

BACKGROUND: There are numerous techniques which attempt to quantify inotropy (or myocardial contractility). None has yet found general acceptance in anaesthesia and critical care as a practical method. We report a novel approach to the determination of inotropy as a bedside procedure which could identify low inotropy states in patients with clinical heart failure. METHODS: We estimated the potential and kinetic energy delivered by the left ventricle using continuous-wave Doppler ultrasound (ultrasonic cardiac output monitor, Uscom, Sydney, Australia) and data available at the point of care. A formula to calculate effective inotropy [Smith-Madigan inotropy index (SMII)] was tested against historical haemodynamic data for 250 control subjects (ASA I patients from preoperative clinic) and 83 patients with acute left ventricular failure (LVF) of New York Heart Association Grade 4 (LVF group). The ratio of potential to kinetic energy (PKR) was investigated as a measure of arterial impedance. RESULTS: Significant differences were found between the control and LVF groups for cardiac index, mean (range)=3.37 (2.84-5.32) vs 1.84 (1.43-2.26) litre min(-1) m(-2); stroke volume index (SVI), 49.2 (39-55) vs 34.3 (23-37) ml m(-2); systemic vascular resistance, 893 (644-1242) vs 1960 (1744-4048) dyn s cm(-5); SMII, 1.78 (1.35-2.24) vs 0.73 (0.43-0.97) W m(-2); and PKR, 29:1 (24-35:1) vs 124:1 (96-174:1), P<0.001 in each case. Normal ranges were calculated for SMII and PKR as mean (+/-1.96) standard deviations, yielding 1.6-2.2 W m(-2) for SMII, and 25-34:1 for PKR. CONCLUSION: The method clearly identified the two clinical groups with no overlap of data points. The discriminant power of SMII and PKR may offer valuable diagnostic methods and monitoring tools in anaesthesia and critical care. This is the first report of normal ranges for SMII and PKR.

You are what you eat, whenever or wherever you eat it: an integrative analysis of fish food habits in Canadian and U.S.A. waters.

The degree to which fish diet differs by season and area, particularly over broad scales, was examined for the first time in temperate, contiguous north-west Atlantic Ocean waters by comparing food habit data for 10 species of fishes collected concurrently during the spring and autumn surveys in the U.S.A. (Gulf of Maine proper and Georges Bank) and in the summer survey in Canada (western Scotian Shelf and Bay of Fundy). For most species, there was a general concurrence among the three seasons and four areas: summer diets had the same dominant prey items as spring and autumn diets. Although a suite of multivariate analyses did elucidate some differences in specific proportions of the diet for these species across seasons and areas, the main prey did not substantially change for most of these species. These results suggest that there are (1) minimal differences in diet across season for these species at these taxonomic resolutions, (2) there are minimal differences in diet geographically for these species and (3) differences across species, as expected, are important. Many fisheries ecosystem and multispecies models are dependent on food habit data, where resolving seasonal and spatial differences in diet remains an important consideration; however, the present work implies that amalgamated estimates of diet from seasonal surveys may be a reasonable approach when no finer seasonal resolution exists, as long as due diligence is exercised.

Biomarkers of Recent Cannabis Use in Blood, Oral Fluid and Breath.

Proving driving under the influence of cannabis (DUIC) is difficult. Establishing a biomarker of recent use to supplement behavioral observations may be a useful alternative strategy. We determined whether cannabinoid concentrations in blood, oral fluid (OF) or breath could identify use within the past 3 h-likely the period of the greatest impairment. In a randomized trial, 191 frequent (≥4/week) and occasional (<4/week) cannabis users smoked one cannabis (placebo [0.02%], or 5.9% or 13.4% Δ9-tetrahydrocannabinol [THC]) cigarette ad libitum. Blood, OF and breath samples were collected prior to and up to 6 h after smoking. Samples were analyzed for 10 cannabinoids in OF, 8 in blood and THC in breath. Frequent users had more residual THC in blood and were more likely to be categorized as 'recently used' prior to smoking; this did not occur in OF. Per se limits ranging from undetectable to 5 ng/mL THC in blood offered limited usefulness as biomarkers of recent use. Cannabinol (CBN, cutoff = 1 ng/mL) in blood offered 100% specificity but only 31.4% sensitivity, resulting in 100% positive predictive value (PPV) and 94.0% negative predictive value (NPV) at 4.3% prevalence; however, CBN may vary by cannabis chemovar. A 10 ng/mL THC cutoff in OF exhibited the overall highest performance to detect its use within 3 h (99.7% specificity, 82.4% sensitivity, 92.5% PPV and 99.2% NPV) but was still detectable in 23.2% of participants ∼4.4 h post-smoking, limiting specificity at later time points. OF THC may be a helpful indicator of recent cannabis intake, but this does not equate to impairment. Behavioral assessment of impairment is still required to determine DUIC. This study only involved cannabis inhalation, and additional research evaluating alternative routes of ingestion (i.e., oral) is needed.

Functional feeding responses of piscivorous fishes from the northeast US continental shelf.

The functional feeding response forms of piscivorous fishes used in multispecies and ecosystem modeling have been questioned because they were mostly conjectural or solely based on laboratory studies. Here, we investigate the functional feeding response of seven species of piscivorous fishes on four species of their prey from the northeast US continental shelf using field data that spans 30 years. Our study confirmed that Holling's types II and III functional responses are the most common functional responses for piscivorous fishes in this region. However, our analyses also revealed that differences exist between piscivorous fishes' functional responses, and, therefore, combining functional responses of piscivores is probably not appropriate in multispecies and ecosystem modeling. In the absence of specific predator-prey functional responses, we suggest that, for cruising, actively attacking predators, a type II functional response is slightly preferable; for a sedentary, ambush predator, a type III functional response is slightly preferable; at low prey densities for a generic fish predator, a type III functional response should be used; and at moderate to high prey densities, either should work sufficiently. Because we have shown that the functional response of a particular predator to individual prey species varies, these relationships must be further evaluated as we continue to develop and employ multispecies and ecosystem modeling.

Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy.

INTRODUCTION: Copper deficiency is an increasingly recognised cause of neurological impairment. This retrospective review highlights clinical and electrodiagnostic findings in patients diagnosed at our institution with copper deficiency. METHODS: Clinical, radiographic and electrodiagnostic findings were reviewed in patients with evidence of copper deficiency. Patients with other potential causes of myelopathy or neuropathy were excluded. RESULTS: The predominant clinical feature in all six patients was a sensory ataxia, resulting in marked gait unsteadiness. Nerve conduction studies and needle EMG were performed in all patients and revealed a mild to moderate distal, axonal, sensorimotor peripheral neuropathy. Median and tibial somatosensory evoked potentials were abnormal in all five patients in which it was performed, showing impaired conduction in central or proximal peripheral somatosensory pathways. CONCLUSIONS: This pattern of electrodiagnostic findings suggests that impairment in somatosensory pathways demonstrated by somatosensory evoked potential testing is the main cause of the sensory ataxia in patients with copper deficiency.

Biological and environmental drivers of trophic ecology in marine fishes - a global perspective.

Dietary niche width and trophic position are key functional traits describing a consumer's trophic ecology and the role it plays in a community. However, our understanding of the environmental and biological drivers of both traits is predominantly derived from theory or geographically restricted studies and lacks a broad empirical evaluation. We calculated the dietary niche width and trophic position of 2,938 marine fishes and examined the relationship of both traits with species' maximum length and geographic range, in addition to species richness, productivity, seasonality and water temperature within their geographic range. We used Generalized Additive Models to assess these relationships across seven distinct marine habitat types. Fishes in reef associated habitats typically had a smaller dietary niche width and foraged at a lower trophic position than those in pelagic or demersal regions. Species richness was negatively related to dietary niche width in each habitat. Species range and maximum length both displayed positive associations with dietary niche width. Trophic position was primarily related to species maximum length but also displayed a non-linear relationship with dietary niche width, whereby species of an intermediate trophic position (3-4) had a higher dietary niche width than obligate herbivores or piscivores. Our results indicate that trophic ecology of fishes is driven by several interlinked factors. Although size is a strong predictor of trophic position and the diversity of preys a species can consume, dietary niche width of fishes is also related to prey and competitor richness suggesting that, at a local level, consumer trophic ecology is determined by a trade-off between environmental drivers and biological traits.

Stroke Volume Monitoring: Novel Continuous Wave Doppler Parameters, Algorithms and Advanced Noninvasive Haemodynamic Concepts.

PURPOSE OF REVIEW: Adequate oxygen delivery is essential for life, with hypoxia resulting in dysfunction, and ultimately death, of the cells, organs and organism. Blood flow delivers the oxygen bound in the blood, while haemodynamics is the science of blood flow. Stroke volume (SV) is the fundamental unit of blood flow, and reflects the interdependent performance of the heart, the vessels and the autonomic nervous system. However, haemodynamic management remains generally poor and predominantly guided by simple blood pressure observations alone. RECENT FINDINGS: Doppler ultrasound measures SV with unequalled clinical precision when operated by trained personnel. Combining SV with BP measurements allows calculation of flow-pressure based measures which better reflect cardiovascular performance and allows personalised physiologic and pathophysiologic modelling consistent with Frank's and Starling's observations. SUMMARY: Doppler SV monitoring and novel flow-pressure parameters may improve our understanding of the cardiovascular system and lead to improved diagnosis and therapy. This review examines the physics and practice of Doppler SV monitoring and its application in advanced haemodynamics.

Copper deficiency myeloneuropathy resembling B12 deficiency: partial resolution of MR imaging findings with copper supplementation.

Copper deficiency has been associated with a clinical syndrome, myeloneuropathy. Radiographic changes resembling B(12) deficiency in the cervical spinal cord have been described. We present a case of copper deficiency myeloneuropathy, with cervical MR imaging findings resembling B(12) deficiency, which partially reversed following copper supplementation. This is, to our knowledge, the first described case of radiographic improvement with copper supplementation.

A 31P-NMR study of the mechanism of and salt effect on Mg2(+)-ATP exchange.

The study of exchange between free and metal-bound ligands by NMR methods is discussed with reference to differentiation between unimolecular dissociation of the metal-bound complex and biomolecular exchange of metal ion between two ligands. This is applied to exchange of ATP4- between the free and Mg2(+)-bound states and problems of interpretation in the presence of a strong kinetic salt effect are discussed. Contrary to a previous report, exchange is inferred to occur mainly via unimolecular dissociation of MgATP2- over a range of temperatures, concentrations, and pH values, which include those expected in vivo. For the model system Mg2(+)-tripolyphosphate, an activation energy of 52 +/- 5 kJ.mol-1, inferred to be that for dissociation of MgTPPH2-, is found for the exchange process.

A 31P-NMR study of mono- and dimagnesium complexes of adenosine 5'-triphosphate and model systems.

31P-NMR chemical shifts and spin-lattice relaxation times of ATP (adenosine 5'-triphosphate), ribose 5'-triphosphate and tripolyphosphate show closely similar behaviour in aqueous solution at pH 7.5 on titration with Mg2+. The results are interpreted in terms of formation of 1 : 1 and 2 : 1 (dimagnesium) complexes with Mg2+ bound exclusively to the triphosphate chain. Stability constants for these complexes are reported. It is suggested that the predominant form of the 1 : 1 complexes has Mg2+ bound in tridentate manner (via non-bridging oxygen) to the alpha, beta and gamma phosphorus atoms; whilst that of the 2 : 1 complexes has each Mg2+ bound in bidentate manner, one to the alpha and beta, and the other to the beta and gamma, phosphorus positions.

Evidence on the role(s) of ATP in the mechanism of nitrogenase, from proton NMR relaxation studies on metal and nucleotide binding to the molybdenum-iron protein.

Interactions between the molybdenum-iron protein (Kp1) of nitrogenase (reduced ferredoxin:dinitrogen oxidoreductase (ATP-hydrolysing,) EC 1.18.2.1) from Klebsiella pneumoniae and the divalent ions, Mn2+, Mg2+, Ca2+ and Ba2+, have been studied by monitoring the water proton NMR relaxation enhancement caused by the paramagnetism of Mn2+. We observed several binding sites for Mn2+, equivalent within experimental error (Kd = 209 +/- 23 microM), increasing in number from 1.0 to 2.9 per molecule in direct proportion to the specific activity of the protein. Metal binding sites on the MoFe protein are therefore essential to the enzymic function of nitrogenase. A maximum of four such sites is inferred for the fully active protein molecule. All manganese sites can alternatively bind the diamagnetic ions studied, the binding being one order-of-magnitude weaker (Kd = 2.2 +/- 0.3 mM for Mg2+; 1.6 +/- 0.2 mM for Ca2+; 3.4 +/- 0.3 mM for Ba2+), ATP and ADP form ternary complexes via Mn2+ with Kpl. The above data and other evidence on MgATP binding are discussed in terms of the site of hydrolysis of ATP during turnover and its possible bridging role between the two protein components of the enzyme.

Nitrogenase of Klebsiella pneumoniae. Water proton NMR relaxation studies on the binding of divalent metal ions and nucleotides to the iron protein.

Interactions between the iron protein, Kp2, of nitrogenase manganese ions, magnesium ions, and the nucleotides ATP or ADP, have been studied in aqueous solution by monitoring the water proton NMR relaxation rate enhancement caused by Mn2+. Binding of Mn2+ to a molecule of Kp2 occurs at four sites, indistinguishable within experimental error, having a Kd = 350 +/- 50 micron. The Mn2+ - Kp2 complex has a low characteristic enhancement (epsilonb = 6 +/- 0.5). All four sites can alternatively bind Mg2+, not necessarily with the same dissociation constant, but with a mean Kd = 1.7 +/- 0.3 mM. Ternary complexes with the configuration EMS or (formula: see text) are formed between Kp2, Mn2+ and nucleotide (ATP or ADP). The ternary complexes with Mg2+ in place of Mn2+ probably have the latter configuration. A novel treatment of enhancement data (a 'high metal' approximation) is given.

Analysis of site-directed mutations in the α-and ß-subunits of Klebsiella pneumoniae nitrogenase.

Using directed mutagenesis, amino acid substitutions have been made in the α- and ß-subunits of the Klebsiella pneumoniae nitrogenase component 1 at positions normally occupied by conserves cysteine or tyrosine residues. Nif', Nif and intermediate pheno-types have been obtained. To extend our earlier biochemical characterization (Kent et al, 1989) the electrophoretic mobiliy of component 1 of the mutant and wild-type nitrogenases has been analysed by non-denaturing gel electrophoresis. The major and minor forms of component 1 separated by this methodology have been probed for by using both polyclonal and monoclonal antibodies. All Nif mutants exhibited a distribution of electrophoretic forms of component 1 comparable to the wild type, and the abundance of the major from found in purified nitrogennase correlated approximately with the specific activity of the extract. In contrast, after electrophoresis, component 1 from Nif mutants exhibited either a major low-mobility from or a fast-moving from. Analysis of co-factor (FeMoco) allowed us to conclude that changing cysteine 275 to alanine in the α-submit produces component 1 defective in its interaction with FeMoco. Substitution of other con-served cysteine residues by alanine appears to prevent early steps in nitrogebnase assembly or to promote degradation. Two single mutations (cysteine89 to alanine in the ß-subunit) which are tightly Nif can be combined to produce a weakly active nitrogenase, indicating regions involved in the interaction between subunits.

The first glimpse of a complex of nitrogenase component proteins by solution X-ray scattering: conformation of the electron transfer transition state complex of Klebsiella pneumoniae nitrogenase.

An essential feature of the mechanism of nitrogenase, the enzyme responsible for biological nitrogen fixation, is the formation of a transient electron transfer complex between the MoFe protein containing the active site at which N2 is reduced, and the Fe protein, which functions as a specific electron donor to the MoFe protein. We have obtained high quality solution X-ray scattering data using synchrotron X-rays of a stable putative electron transfer complex, (MoFe-protein)(Fe-protein.ADP.AIF4)2, of Klebsiella pneumoniae and used the model-independent approach based on the multipole expansion method to provide a stable and unique shape restoration at approximately 15 A resolution. The biological significance of this first molecular structure of a nitrogenase complex is discussed.

New insights into structure-function relationships in nitrogenase: A 1.6 A resolution X-ray crystallographic study of Klebsiella pneumoniae MoFe-protein.

The X-ray crystal structure of Klebsiella pneumoniae nitrogenase component 1 (Kp1) has been determined and refined to a resolution of 1.6 A, the highest resolution reported for any nitrogenase structure. Models derived from three 1.6 A resolution X-ray data sets are described; two represent distinct oxidation states, whilst the third appears to be a mixture of both oxidized and reduced states (or perhaps an intermediate state). The structures of the protein and the iron-molybdenum cofactor (FeMoco) appear to be largely unaffected by the redox status, although the movement of Ser beta90 and a surface helix in the beta subunit may be of functional significance. By contrast, the 8Fe-7S P-cluster undergoes discrete conformational changes involving the movement of two iron atoms. Comparisons with known component 1 structures reveal subtle differences in the FeMoco environment, which could account for the lower midpoint potential of this cluster in Kp1. Furthermore, a non-proline- cis peptide bond has been identified in the alpha subunit that may have a functional role. It is within 10 A of the FeMoco and may have been overlooked in other component 1 models. Finally, metal-metal and metal-sulphur distances within the metal clusters agree well with values derived from EXAFS studies, although they are generally longer than the values reported for the closely related protein from Azotobacter vinelandii. A number of bonds between the clusters and their ligands are distinctly longer than the EXAFS values, in particular, those involving the molybdenum atom of the FeMoco.

Structural and kinetic evidence for an ordered mechanism of copper nitrite reductase.

The crystallographic structures of several copper-containing nitrite reductases are now available. Despite this wealth of structural data, no definitive information is available as to whether the reaction proceeds by an ordered mechanism where nitrite binds to the oxidised type 2 site, followed by an internal electron transfer from the type 1 Cu, or whether binding occurs to the reduced type 2 Cu centre, or a random mechanism operates. We present here the first structural information on both types of Cu centres for the reduced form of NiR from Alcaligenes xylosoxidans (AxNiR) using X-ray absorption spectroscopy. The reduced type 2 Cu site EXAFS shows striking similarity to the EXAFS data for reduced bovine superoxide dismutase (Cu2Zn2 SOD), providing strong evidence for the loss of the water molecule from the catalytic Cu site in NiR on reduction resulting in a tri-coordinate Cu site similar to that in Cu2Zn2 SOD. The reduced type 2 Cu site of AxNiR is shown to be unable to bind inhibitory ligands such as azide, and to react very sluggishly with nitrite leading to only a slow re-oxidation of the the type 1 centre. These observations provide strong evidence that turnover of AxNiR proceeds by an ordered mechanism in which nitrite binds to the oxidised type 2 Cu centres before electron transfer from the reduced type 1 centre occurs. We propose that the two links between the Cu sites of AxNiR, namely His129-Cys130 and His89-Asp92-His94 are utilised for electron transfer and for communicating the status of the type 2 Cu site, respectively. Nitrite binding at type 2 Cu is sensed by the proton abstracting group Asp92 and the type 2 Cu ligand His94, and relayed to the type 1 Cu site via His89 thus triggering an internal electron transfer. The similarity of the type 2 Cu NiR catalytic site to the reduced Cu site of SOD is examined in some detail together with the biochemical evidence for the SOD activity of AxNiR.

Medical equipment libraries: implementation, experience and user satisfaction.

The hospital-wide pooling and sharing of certain types of medical equipment can lead to both significant improvements in patient safety and financial advantages when compared with a department or ward-level equipment ownership system. In September 2003, a Medical Equipment Loan Service (MELS) was established, focusing initially on infusion pumps. The aims and expected benefits included; improving availability of equipment for both patients and clinical users, managing and reducing clinical risk, reducing equipment diversity, improving equipment management and reducing the overall cost of equipment provision. A user survey was carried out in 2005 and repeated in 2011. The results showed wide and continued satisfaction with the service. The process and difficulties of establishing the service and its development to include additional types of equipment are described. The benefits of managing medical equipment which is in widespread general use, through a MELS as part of a Clinical Engineering Department, are presented.