Phosphodiesterase PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

Background and purpose Phosphodiesterases PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1μM) or PDE4 inhibitor rolipram (1-10μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1Hz. The effects of (-)-noradrenaline, mediated through β1-adrenoceptors (β2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2-adrenoceptors (β1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P=0.037) of the positive inotropic effects of (-)-adrenaline (0.78±0.12 log units) than (-)-noradrenaline (0.47±0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1- and β2-adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2-adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

Intra-arterial waveform analysis: a study of senior nurse knowledge in a general intensive care unit

The aim of this small-scale study was to assess what knowledge senior nurses within a general intensive care unit (GICU) had in relation to intra-arterial blood pressure (IABP) waveform analysis. Its core objective was: To assess what knowledge was held by the senior nursing team with regard to arterial waveform interpretation, arterial waveform morphology and the technical aspects associated with arterial waveform monitoring.

Advanced arterial blood gas analysis in septic shock : a Singaporean nursing case review.

Introduction The admission to the Intensive Care Unit with a diagnosis of sepsis and/or septic shock is not uncommon. The aim of this article is to present a nursing case review of a patient admitted to the intensive care unit with a diagnosis of septic shock and the use of bedside acid–base formulae to inform clinical decision making. Method We chose to use a case review. This method is useful in reporting unusual or rare cases and is typically seen more in medicine than in nursing. Discussion The gentleman in question was a self-presentation with a short history of fever and worsening shortness of breath. His condition worsened where he required admission to the intensive care unit. The use of ‘advanced’ acid–base interpretation to guide his nursing care provided a platform from which to advance a deeper understanding of the intricacies the critically ill patient often presents. Conclusion The use of case review is enlightening in understanding the disease process and the decision-making that accompanies this. The lessons learnt are applicable to a wider nursing audience because understanding acid–base physiology is beneficial in supporting and advancing critical care nursing practice.

Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking

Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol- and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucrose-seeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanol-seeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

Design, characterisation and in vivo testing of a new, adjustable stiffness, external fixator for the rat femur

Very little is known about the infl uence of the mechanical environment on the healing of large segmental defects. This partly reflects the lack of standardised, well characterised technologies to enable such studies. Here we report the design, construction and characterisation of a novel external fixator for use in conjunction with rat femoral defects. This device not only imposes a predetermined axial stiffness on the lesion, but also enables the stiffness to be changed during the healing process. The main frame of the fi xator consists of polyethylethylketone with titanium alloy mounting pins. The stiffness of the fi xator is determined by interchangeable connection elements of different thicknesses. Fixators were shown to stabilise 5 mm femoral defects in rats in vivo for at least 8 weeks during unrestricted cage activity. No distortion or infections, including pin infections, were noted. The healing process was simulated in vitro by inserting into a 5 mm femoral defect, materials whose Young’s moduli approximated those of the different tissues present in regenerating bone. These studies confirmed that, although the external fixator is the major determinant of axial stiffness during the early phase of healing, the regenerate within the lesion subsequently dominates this property. There is much clinical interest in altering the mechanics of the defect to enhance bone healing. Our data suggest that, if alteration of the mechanical environment is to be used to modulate the healing of large segmental defects, this needs to be performed before the tissue properties become dominant.

Management based on exhaled nitric oxidelevels adjusted for atopy reduces asthma exacerbations in children : A dual centre randomised controlled trial

While several randomised control trials (RCTs) have evaluated the use of fractional exhaled nitric oxide (FeNO) to improve asthma outcomes, none used FeNO cut-offs adjusted for atopy, a determinant of FeNO levels. In a dual centre RCT, we assessed whether a treatment strategy based on FeNO levels, adjusted for atopy, reduces asthma exacerbations compared with the symptoms-based management (controls). Children with asthma from hospital clinics of two hospitals were randomly allocated to receive an a-priori determined treatment hierarchy based on symptoms or FeNO levels. There was a 2-week run-in period and they were then reviewed ten times over 12-months. The primary outcome was the number of children with exacerbations over 12-months. Sixty-three children were randomised (FeNO=31, controls=32); 55 (86%) completed the study. Although we did achieve our planned sample size, significantly fewer children in the FeNO group (6 of 27) had an asthma exacerbation compared to controls (15 of 28), p=0.021; number to treat for benefit=4 (95%CI 3-24). There was no difference between groups for any secondary outcomes (quality of life, symptoms, FEV1). The final daily inhaled corticosteroids (ICS) dose was significantly (p=0.037) higher in the FeNO group (median 400µg, IQR 250-600) compared to the controls (200, IQR100-400). Taking atopy into account when using FeNO to tailor asthma medications is likely beneficial in reducing the number of children with severe exacerbations at the expense of increased ICS use. However, the strategy is unlikely beneficial for improving asthma control. A larger study is required to confirm or refute our findings.

High temperature reduces apple fruit colour via modulation of the anthocyanin regulatory complex

The biosynthesis of anthocyanin in many plants is affected by environmental conditions. In apple (Malus×domestica Borkh.), concentrations of fruit anthocyanins are lower under hot climatic conditions. We examined the anthocyanin accumulation in the peel of maturing 'Mondial Gala' and 'Royal Gala' apples, grown in both temperate and hot climates, and using artificial heating of on-tree fruit. Heat caused a dramatic reduction of both peel anthocyanin concentration and transcripts of the genes of the anthocyanin biosynthetic pathway. Heating fruit rapidly reduced expression of the R2R3 MYB transcription factor (MYB10) responsible for coordinative regulation for red skin colour, as well as expression of other genes in the transcriptional activation complex. A single night of low temperatures is sufficient to elicit a large increase in transcription of MYB10 and consequently the biosynthetic pathway. Candidate genes that can repress anthocyanin biosynthesis did not appear to be responsible for reductions in anthocyanin content. We propose that temperature-induced regulation of anthocyanin biosynthesis is primarily caused by altered transcript levels of the activating anthocyanin regulatory complex.

A collagen prolyl 4-hydroxylase inhibitor reduces adhesions after tendon injury

Collagen synthesis inhibition potentially can reduce adhesion formation after tendon injury but also may affect cutaneous wound healing. We hypothesized that a novel orally administered collagen synthesis inhibitor (CPHI-I) would substantially reduce flexor tendon adhesions after injury, without any clinically important effect on cutaneous wound healing. The experiments were performed in a rat model with an in-continuity crush injury model in the rat hindfoot flexor tendon to provoke adhesion formation. Assays of dermal collagen production and the rate of healing of an excised wound were performed to assess cutaneous wound healing. Animals in the treatment groups received CPHI-I for 1, 2, or 6 weeks and were assessed at either 2 or 6 weeks. The work of flexion in the injured digit was reduced in the CPHI-I-treated animals compared with control animals, (0.188 J versus 0.0307 J at 2 weeks, and 0.0231 J versus 0.0331 J at 6 weeks) The cutaneous wound healing rate was similar in all animals, but dermal collagen synthesis was reduced in the treated animals. The CPHI-I seems to reduce tendon adhesion, and although collagen synthesis was reduced in cutaneous wounds, CPHI-I did not retard wound healing.

Room-temperature, atmospheric plasma needle reduces adenovirus gene expression in HEK 293A host cells

Room-temperature, atmospheric-pressure plasma needle treatment is used to effectively minimize the adenovirus (AdV) infectivity as quantified by the dramatic reduction of its gene expression in HEK 293A primary human embryonic kidney cells studied by green fluorescent protein imaging. The AdV titer is reduced by two orders of magnitude within only 8 min of the plasma exposure. This effect is due to longer lifetimes and higher interaction efficacy of the plasma-generated reactive species in confined space exposed to the plasma rather than thermal effects commonly utilized in pathogen inactivation. This generic approach is promising for the next-generation anti-viral treatments and imunotherapies.

Arterial short-term travel time prediction using Bluetooth data

This project recognized lack of data analysis and travel time prediction on arterials as the main gap in the current literature. For this purpose it first investigated reliability of data gathered by Bluetooth technology as a new cost effective method for data collection on arterial roads. Then by considering the similarity among varieties of daily travel time on different arterial routes, created a SARIMA model to predict future travel time values. Based on this research outcome, the created model can be applied for online short term travel time prediction in future.

Semantic context and visual feature effects in object naming : an fMRI study using arterial spin labeling

Previous behavioral studies reported a robust effect of increased naming latencies when objects to be named were blocked within semantic category, compared to items blocked between category. This semantic context effect has been attributed to various mechanisms including inhibition or excitation of lexico-semantic representations and incremental learning of associations between semantic features and names, and is hypothesized to increase demands on verbal self-monitoring during speech production. Objects within categories also share many visual structural features, introducing a potential confound when interpreting the level at which the context effect might occur. Consistent with previous findings, we report a significant increase in response latencies when naming categorically related objects within blocks, an effect associated with increased perfusion fMRI signal bilaterally in the hippocampus and in the left middle to posterior superior temporal cortex. No perfusion changes were observed in the middle section of the left middle temporal cortex, a region associated with retrieval of lexical-semantic information in previous object naming studies. Although a manipulation of visual feature similarity did not influence naming latencies, we observed perfusion increases in the perirhinal cortex for naming objects with similar visual features that interacted with the semantic context in which objects were named. These results provide support for the view that the semantic context effect in object naming occurs due to an incremental learning mechanism, and involves increased demands on verbal self-monitoring.

The effect of intervertebral staple insertion on bovine spine segment stiffness

Introduction There is growing interest in the biomechanics of ‘fusionless’ implant constructs used for deformity correction in the thoracic spine. Intervertebral stapling is a leading method of fusionless corrective surgery. Although used for a number of years, there is limited evidence as to the effect these staples have on the stiffness of the functional spinal unit. Materials and Methods Thoracic spines from 6-8 week old calves were dissected and divided into motion segments including levels T4-T11 (n=14). Each segment was potted in polymethylemethacrylate. An Instron Biaxial materials testing machine with a custom made jig was used for testing. The segments were tested in flexion/extension, lateral bending and axial rotation at 37⁰C and 100% humidity, using moment control to a maximum 1.75 Nm with a loading rate of 0.3 Nm per second. This torque was found sufficient to achieve physiologically representative ranges of movement. The segments were initially tested uninstrumented with data collected from the tenth load cycle. Next a left anterolateral Shape Memory Alloy (SMA) staple was inserted (Medtronic Sofamor Danek, USA). Biomechanical testing was repeated as before with data collected from the tenth load cycle. Results In flexion/extension there was an insignificant drop in stiffness of 3% (p=0.478). In lateral bending there was a significant drop in stiffness of 21% (p<0.001). This was mainly in lateral bending away from the staple, where the stiffness reduced by 30% (p<0.001). This was in contrast to lateral bending towards the staple where it dropped by 12% which was still statistically significant (p=0.036). In axial rotation there was an overall near significant drop in stiffness of 11% (p=0.076). However, this was more towards the side of the staple measuring a decrease of 14% as opposed to 8% away from the staple. In both cases it was a statistically insignificant drop (p=0.134 and p=0.352 respectively). Conclusion Insertion of intervertebral SMA staples results in a significant reduction in motion segment stiffness in lateral bending especially in the direction away from the staple. The staple had less effect on axial rotation stiffness and minimal effect on flexion/extension stiffness.

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.

Investigating the effect of internal fixation stiffness on metaphyseal fracture healing in a mouse model

This project examined the differences in healing of metaphyseal bone, when the implants of variable stiffness are used for fracture fixation. This knowledge is important in development of novel orthopaedic implants, used in orthopaedic surgery to stabilise the fractures. Dr Koval used a mouse model to create a fracture, and then assessed its healing with a combination of mechanical testing, microcomputed tomography and histomorphometric examination.