Treatment threshold for intra-operative hypotension in clinical practice-a prospective cohort study in older patients in the UK.

Intra-operative hypotension frequently complicates anaesthesia in older patients and is implicated in peri-operative organ hypoperfusion and injury. The prevalence and corresponding treatment thresholds of hypotension are incompletely described in the UK. This study aimed to identify prevalence of intra-operative hypotension and its treatment thresholds in UK practice. Patients aged ≥ 65 years were studied prospectively from 196 UK hospitals within a 48-hour timeframe. The primary outcome was the incidence of hypotension (mean arterial pressure <65 mmHg; systolic blood pressure reduction >20%; systolic blood pressure <100 mmHg). Secondary outcomes included the treatment blood pressure threshold for vasopressors; incidence of acute kidney injury; myocardial injury; stroke; and in-hospital mortality. Additionally, anaesthetists providing care for included patients were asked to complete a survey assessing their intended treatment thresholds for hypotension. Data were collected from 4750 patients. Hypotension affected 61.0% of patients when defined as mean arterial pressure <65 mmHg, 91.3% of patients had >20% reduction in systolic blood pressure from baseline and 77.5% systolic blood pressure <100 mmHg. The mean (SD) blood pressure triggering vasopressor therapy was mean arterial pressure 64.2 (11.6) mmHg and the mean (SD) stated intended treatment threshold from the survey was mean arterial pressure 60.6 (9.7) mmHg. A composite adverse outcome of myocardial injury, kidney injury, stroke or death affected 345 patients (7.3%). In this representative sample of UK peri-operative practice, the majority of older patients experienced intra-operative hypotension and treatment was delivered below suggested thresholds. This highlights both potential for intra-operative organ injury and substantial opportunity for improving treatment of intra-operative hypotension.

Lower body negative pressure reduces jugular and portal vein volumes and counteracts the elevation of middle cerebral vein velocity during long-duration spaceflight.

Cephalad fluid shifts in space have been hypothesized to cause the spaceflight-associated neuro-ocular syndrome (SANS) by increasing the intracranial-ocular translaminal pressure gradient. Lower body negative pressure (LBNP) can be used to shift upper-body blood and other fluids toward the legs during spaceflight. We hypothesized that microgravity would increase jugular vein volume (JVvol), portal vein cross-sectional area (PV), and intracranial venous blood velocity (MCV) and that LBNP application would return these variables toward preflight levels. Data were collected from 14 subjects (11 males) before and during long-duration International Space Station (ISS) spaceflights. Ultrasound measures of JVvol, PV, and MCV were acquired while seated and supine before flight and early during spaceflight at day 45 (FD45) and late at day 150 (FD150) with and without LBNP. JVvol increased from preflight supine and seated postures (46 ± 48% and 646 ± 595% on FD45 and 43 ± 43% and 702 ± 631% on FD150, P < 0.05), MCV increased from preflight supine (44 ± 31% on FD45 and 115 ± 116% on FD150, P < 0.05), and PV increased from preflight supine and seated (51 ± 56% on FD45 and 100 ± 74% on FD150, P < 0.05). Inflight LBNP of -25 mmHg restored JVvol and MCV to preflight supine level and PV to preflight seated level. Elevated JVvol confirms the sustained neck-head blood engorgement inflight, whereas increased PV area supports the fluid shift at the splanchnic level. Also, MCV increased potentially due to reduced lumen diameter. LBNP, returning variables to preflight levels, may be an effective countermeasure.NEW & NOTEWORTHY Microgravity-induced fluid shifts markedly enlarge jugular and portal veins and increase cerebral vein velocity. These findings demonstrate a marked flow engorgement at neck and splanchnic levels and may suggest compression of the cerebral veins by the brain tissue in space. LBNP (-25 mmHg for 30 min) returns these changes to preflight levels and, thus, reduces the associated flow and tissue disturbances.

Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase.

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 µM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.

Caudwell Xtreme Everest: An Overview.

The Caudwell Xtreme Everest (CXE) expedition in the spring of 2007 systematically studied 222 healthy volunteers as they ascended from sea level to Everest Base Camp (5300 m). A subgroup of climbing investigators ascended higher on Everest and obtained physiological measurements up to an altitude of 8400 m. The aim of the study was to explore inter-individual variation in response to environmental hypobaric hypoxia in order to understand better the pathophysiology of critically ill patients and other patients in whom hypoxaemia and cellular hypoxia are prevalent. This paper describes the aims, study characteristics, organization and management of the CXE expedition.

Systemic oxygen extraction during exercise at high altitude.

BACKGROUND: Classic teaching suggests that diminished availability of oxygen leads to increased tissue oxygen extraction yet evidence to support this notion in the context of hypoxaemia, as opposed to anaemia or cardiac failure, is limited. METHODS: At 75 m above sea level, and after 7-8 days of acclimatization to 4559 m, systemic oxygen extraction [C(a-v)O2] was calculated in five participants at rest and at peak exercise. Absolute [C(a-v)O2] was calculated by subtracting central venous oxygen content (CcvO2) from arterial oxygen content [Formula: see text] in blood sampled from central venous and peripheral arterial catheters, respectively. Oxygen uptake [Formula: see text] was determined from expired gas analysis during exercise. RESULTS: Ascent to altitude resulted in significant hypoxaemia; median (range) [Formula: see text] 87.1 (82.5-90.7)% and [Formula: see text] 6.6 (5.7-6.8) kPa. While absolute C(a-v)O2 was reduced at maximum exercise at 4559 m [83.9 (67.5-120.9) ml litre(-1) vs 99.6 (88.0-151.3) ml litre(-1) at 75 m, P=0.043], there was no change in oxygen extraction ratio (OER) [C(a-v)O2/CaO2] between the two altitudes [0.52 (0.48-0.71) at 4559 m and 0.53 (0.49-0.73) at 75 m, P=0.500]. Comparison of C(a-v)O2 at peak [Formula: see text] at 4559 m and the equivalent [Formula: see text] at sea level for each participant also revealed no significant difference [83.9 (67.5-120.9) ml litre(1) vs 81.2 (73.0-120.7) ml litre(-1), respectively, P=0.225]. CONCLUSION: In acclimatized individuals at 4559 m, there was a decline in maximum absolute C(a-v)O2 during exercise but no alteration in OER calculated using central venous oxygen measurements. This suggests that oxygen extraction may have become limited after exposure to 7-8 days of hypoxaemia.

Vulnerability in the perioperative patient: a concept analysis.

This study aims to report the analysis of the concept of perioperative vulnerability. Literature searches were conducted in databases CINAHL, Medline, PsychINFO, OVID, InterNurse, as well as a manual library search from article reference lists. Search terms were restricted to 'concept analysis', 'vulnerability', 'perioperative', 'patient' and 'perioperative patient'. Retrieved literature was analysed using the Walker & Advant (2005) concept analysis framework. Based on the concept analysis, vulnerability can be seen as having both physical and psychological elements and can be influenced by personal traits. Vulnerability is affected by previous experiences, perceptions of life, disease and ultimately the level of control an individual has over a given situation. The study concludes that inclusion of the concept of vulnerability within both pre- and post-registration training programmes would facilitate awareness of the issues surrounding perioperative vulnerability and the need to plan individualised care accordingly. It is hoped that this analysis will inspire further research and theoretical underpinning of perioperative practice, facilitating the development of new ways to manage vulnerability that will benefit individual patients, develop practice and promote positive patient outcomes.

Anaesthetic nurse specialist role: leading and facilitation in clinical practice.

Leadership and its effectiveness is becoming more prevalent within the nursing profession with anaesthetic nurse specialists showing their ability to lead, inspire and motivate others to work towards a shared vision in the rapidly changing peri-anaesthesia environment. Anaesthetic nurse specialists must therefore be aware of their personal leadership skills and continually develop these within clinical practice. They are also well placed regarding the facilitation of learning.

Controlling the formation of a monolayer of cytochrome P450 reductase onto Au surfaces.

The conditions necessary for the formation of a monolayer and a bilayer of a mutated form (P499C) of human cytochrome P450 reductase on a Au(110)/electrolyte interface have been determined using a quartz crystal microbalance with dissipation, atomic force microscopy, and reflection anisotropy spectroscopy (RAS). The molecules adsorb through a Au-S linkage and, for the monolayer, adopt an ordered structure on the Au(110) substrate in which the optical axes of the dipoles contributing to the RAS signal are aligned roughly along the optical axes of the Au(110) substrate. Differences between the absorption spectrum of the molecules in a solution and the RAS profile of the adsorbed monolayer are attributed to surface order in the orientation of dipoles that contribute in the low energy region of the spectrum, a roughly vertical orientation on the surface of the long axes of the isoalloxazine rings and the lack of any preferred orientation in the molecular structure of the dipoles in the aromatic amino acids. Our studies establish an important proof of principle for immobilizing large biological macromolecules to gold surfaces. This opens up detailed studies of the dynamics of biological macromolecules by RAS, which have general applications in studies of biological redox chemistry that are coupled to protein dynamics.

A rhesus macaque model of Streptococcus pneumoniae carriage.

BACKGROUND: Nasopharyngeal colonization by Streptococcus pneumoniae precedes pneumococcal disease. Elucidation of procedures to prevent or eradicate nasopharyngeal carriage in a model akin to the human would help to diminish the incidence of both pneumonia and invasive pneumococcal disease. METHODS: We conducted a survey of the nasopharynx of infant rhesus macaques from our breeding colony, in search of natural carriers of S. pneumoniae. We also attempted experimental induction of colonization, by nasopharyngeal instillation of a human S. pneumoniae strain (19F). RESULTS: None of 158 colony animals surveyed carried S. pneumoniae in the nasopharynx. Colonization was induced in eight of eight infant rhesus by nasopharyngeal instillation and lasted 2weeks in 100% of the animals and 7weeks in more than 60%. CONCLUSION: Rhesus macaques are probably not natural carriers of S. pneumoniae. The high rate and duration of colonization obtained in our experiments indicates that the rhesus macaque will serve as a human-like carriage model.

Optical reflectance anisotropy of the growth of Fe monolayers on W(110).

We report measurements of the optical anisotropy of Fe layers grown on the W(110) surface using reflection anisotropy spectroscopy (RAS). As the first monolayer of Fe is deposited onto W(110), the resonance-like RAS profile of the clean surface is reduced in intensity. We find evidence for the surface state on W(110) surviving as an interface state following Fe deposition. We observe an anisotropic optical response from Fe layers grown on top of the first two monolayers, where a broad peak at 3 eV dominates the RAS response. The results are simulated in terms of a layered Fresnel reflection model incorporating either a strained Fe overlayer or an Fe overlayer whose dielectric properties are approximated by a simple Lorentzian oscillator. Both approaches are found to produce simulated RA spectra that are in good agreement with experiment. The former approach provides evidence that RAS can detect anisotropy in strained overlayers and that 7 ML films have bulk-like electronic and optical properties.

Reflection anisotropy spectroscopy of the oxidized diamond (001) surface.

We report reflection anisotropy spectroscopy (RAS) measurements of the oxidized (001) surface of a type IIb natural diamond. These measurements were made possible due to recent developments in diamond surface preparation. We compare RAS results from the hydrogenated, clean and oxidized C(001) surface and demonstrate that RAS is sensitive to the structural transition of the surface from the 2 × 1 reconstruction of the clean surface to the 1 × 1 reconstruction of the oxidized surface.

Optical reflectance anisotropy of the Si/Cu(110) surface alloy.

Measurements of the optical reflectance anisotropy (RA) of the Si/Cu(110)-c(2 × 2) surface alloy are reported. Significant changes in the RA response of Cu(110) are observed upon the formation of the surface alloy, and with the growth of one-dimensional (1D) anisotropic Si chains on top of the surface alloy. The transitions between the surface states near the Fermi level (E(F)) at the [Formula: see text] symmetry point on the clean Cu(110) surface are no longer observed in RA spectra of 0.3 ML Si coverage. Peaks in RA spectra arising from transitions between surface-modified bands near E(F) at the L point are found to be sensitive to the formation of the surface alloy. The RA response of the c(2 × 2) surface alloy from 3.0 to 5.5 eV is simulated using a simple three-phase derivative model. The addition of an overlayer phase to this model makes it possible to simulate higher coverage Si/Cu RA profiles where 1D Si chains cover the surface alloy. The success of the models, in which discrete phases contribute to the RA response, supports the view that the Si chains grow on top of the intact c(2 × 2) alloy. Depositing between 1.2 and 1.8 ML Si results in no change to the RA spectroscopy signal, indicating that the signal remains sensitive to the covered alloy interface.

Effects of a nanoparticulate silica substrate on cell attachment of Candida albicans.

AIMS: To investigate the influence of silica nanoparticles on the attachment and growth of Candida albicans cells. METHODS AND RESULTS: Spherical silica nanoparticles with diameters of 4, 7, 14 or 21 nm were attached to tissue culture polystyrene by a polycationic binding layer using a simple deposition procedure. The modified surfaces were shown to reduce the attachment and growth of C. albicans cells by a range of different measurements including microscopy, staining cells and measuring the amount of dye taken up and total cell activity measured using a dye reduction assay. For those cells that did attach and grow, the nanoparticle-coated surface inhibited the yeast to hyphal transition that is induced in the presence of serum. The greatest effect was observed for 7 and 14 nm diameter silica particles and we propose that the mechanism for these effects are related to either the topography of the surface or the slow dissolution of the bound silica. CONCLUSIONS: The attachment and growth of C. albicans is reduced by surface modification with silica nanoparticles. SIGNIFICANCE AND IMPACT OF THE STUDY: The modification of surfaces by nanoparticulate coatings is a simple process that may have applications in reducing the prevalence of Candida sp. cells on medical devices thus, limiting the incidence of this pathogenic yeast in clinical environments.

Glycolysis inhibition for anticancer treatment.

Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

Orientation of ordered structures of cytosine and cytidine -monophosphate adsorbed at Au(110)/liquid interfaces.

It is demonstrated using reflection anisotropy spectroscopy that the adsorption of cytosine and cytidine -monophosphate at the Au(110) 1 x 2/electrolyte interface gives rise to ordered structures in which the base is oriented vertical to the surface and parallel to the [110] axis of the Au(110) plane.

Genotype and subtype analyses of Cryptosporidium isolates from dairy calves and humans in Ontario.

To assess the importance of dairy cattle as a source of human Cryptosporidium infections in Ontario, Canada, 44 Cryptosporidium isolates from neonatal dairy calves and 11 from sporadic human cases of cryptosporidiosis in the province were genotyped by PCR-RFLP analyses of the Cryptosporidium oocyst wall protein (COWP) and 18S rRNA genes. Isolates were also subtyped by sequence analysis of the 60-kDa glycoprotein (GP60) gene. All bovine isolates successfully subtyped belonged to Cryptosporidium parvum subtype family (allele) IIa. Seven subtypes of this family were identified among the bovine isolates. Four human isolates were Cryptosporidium hominis, of alleles Ia, Id, and Ie. Of the remaining seven human specimens, four were C. parvum allele IIa, two were C. parvum of an undetermined subtype, and one was identified as Cryptosporidium cervine genotype. Three of the C. parvum isolates from humans were the same subtypes as isolates from the calves. These findings suggest that cattle and other ruminants may be a source of sporadic human infections in Ontario. This is the first published description of Cryptosporidium genotypes and subtypes in Ontario, and is the second published report of human infection with Cryptosporidium cervine genotype.

Adrenergic nerves mediate the venoconstrictor response to PVN stimulation.

Veins play an important role in the control of venous return, cardiac output and cardiovascular homeostasis. However, the central nervous system sites and effector systems involved in modulating venous function remain to be fully elucidated. The hypothalamic paraventricular nucleus (PVN) is an important site modulating autonomic outflow to the cardiovascular system. Venous tone can be modulated by sympathetic nerves or by adrenal catecholamines. The present study assessed the relative contribution of these autonomic effector systems to the venoconstrictor response elicited by stimulation of the hypothalamic paraventricular nucleus. Male Sprague-Dawley rats were subjected to sham operation or bilateral adrenal demedullation fitted with PVN guide cannulae and fitted with catheters for recording arterial pressure (AP) and intrathoracic vena caval pressure (VP). A latex balloon was advanced into the right atrium. MCFP was calculated from the AP and VP recorded after 4 s of right atrial occlusion. MCFP = VP + (AP - VP)/60. Mean arterial pressure (MAP), heart rate (HR), VP and MCFP responses to injections of BMI (25 ng/side) into the PVN were recorded from conscious rats to avoid the complicating effects of anesthesia. In sham-operated rats, injection of BMI into the PVN increased MAP by 13 +/- 3 mm Hg and HR by 56 +/- 6 bpm. MCFP was also increased significantly by 0.98 +/- 0.15 mm Hg indicating an increase in venomotor tone. Adrenal medullectomy did not affect the pressor (DeltaMAP = 12 +/- 2 mm Hg), tachycardic (DeltaHR = 48 +/- 7 bpm) or venoconstrictor (DeltaMCFP = 0.73 +/- 0.11 mm Hg) responses. Ganglionic blockade abolished the PVN-induced responses in both groups of rats. In a separate group, pretreatment with the adrenergic neuron blocker, guanethidine (20 mg/kg), also abolished the PVN-mediated venoconstrictor responses. Conversely, selective beta2 adrenergic receptor blockade did not affect MCFP responses to BMI. These data indicate that adrenomedullary catecholamines are not necessary for full expression of the venoconstrictor response to PVN stimulation.

Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations.

Sex differences in the degree of high blood pressure have been described in several forms of experimental animal models of hypertension. However, the influence of sex on angiotensin II-induced hypertension has not been studied. In the present study, we investigated and compared the effects of chronic angiotensin II treatment on blood pressure and vascular function in male and female rats. Chronic treatment with angiotensin II (0.7 mg/kg daily for 10 d) significantly raised arterial blood pressure in male but not female Sprague-Dawley rats; it upregulated the NAD(P)H oxidase gp67 phox subunit in the aorta of male but not female rats; and it exaggerated the vasoconstrictor responses to norepinephrine and serotonin in the mesenteric vascular bed (MVB) of male but not female rats. Vasodilator responses to acetylcholine (ACh) but not papaverine (PPV) or isoprenaline (ISO) were reduced in the MVB of angiotensin II-treated male but not female rats. ACh, but not PPV or ISO dilatory responses were potentiated in the MVB of angiotensin II-treated female rats. The present findings demonstrate that exogenous angiotensin II upregulates aortic NAD(P)H oxidase gp67 phox subunit, and induces hypertension and mesenteric vascular dysfunction only in male rats.