Search

Atrial fibrillation (AF) is the most common arrhythmia worldwide. Data regarding 30-day readmission following index admission for AF in the developing world are poorly described.

Electrocardiogram (ECG) delineation to identify the fiducial points of ECG segments, plays an important role in cardiovascular diagnosis and care. Whilst deep delineation frameworks have been deployed within the literature, several factors still hinder their development: (a) data availability: the capacity of deep learning models to generalise is limited by the amount of available data; (b) morphology variations: ECG complexes vary, even within the same person, which degrades the performance of conventional deep learning models. To address these concerns, we present a large-scale 12-leads ECG dataset, ICDIRS, to train and evaluate a novel deep delineation model-ECGVEDNET. ICDIRS is a large-scale ECG dataset with 156,145 QRS onset annotations and 156,145 T peak annotations. ECGVEDNET is a novel variational encoder-decoder network designed to address morphology variations. In ECGVEDNET, we construct a well-regularized latent space, in which the latent features of ECG follow a regular distribution and present smaller morphology variations than in the raw data space. Finally, a transfer learning framework is proposed to transfer the knowledge learned on ICDIRS to smaller datasets. On ICDIRS, ECGVEDNET achieves accuracy of 86.28%/88.31% within 5/10 ms tolerance for QRS onset and accuracy of 89.94%/91.16% within 5/10 ms tolerance for T peak. On QTDB, the average time errors computed for QRS onset and T peak are −1.86 $\pm$ 8.02 ms and −0.50 $\pm$ 12.96 ms, respectively, achieving state-of-the-art performances on both large and small-scale datasets. We will release the source code and the pre-trained model on ICDIRS once accepted.

River water quality is crucial to ecosystem health and water security, yet its deterioration under climate change is often overlooked in climate risk assessments. Here we review how climate change influences river water quality via persistent, gradual shifts and episodic, intense extreme events. Although distinct in magnitude, intensity and duration, these changes modulate the structure and hydro-biogeochemical processes on land and in rivers, hence reshaping land–river connectivity and the quality of river waters. To advance understanding of and forecasting capabilities for water quality in future climates, it is essential to perceive land and rivers as interconnected systems. It is also vital to prioritize research under climate extremes, where the dynamics of water quality often challenge existing theories and models and call for shifts in conceptual paradigms.

The EQ-5D is the first validated questionnaire to assess quality-of-life (QoL) in atrial fibrillation (AF) patients in Syria.

Dilated cardiomyopathy (DCM) is a common yet challenging cardiac disease. Great strides have been made in improving DCM prognosis due to heart failure but sudden cardiac death (SCD) due to ventricular arrhythmias remains significant and challenging to predict. High-risk patients can be effectively managed with implantable cardioverter defibrillators (ICDs) but because identification of what is high risk is very limited, many patients unnecessarily experience the morbidity associated with an ICD implant and many others are not identified and have preventable mortality. Current guidelines recommend use of left ventricular ejection fraction and New York Heart Association class as the main markers of risk stratification to identify patients who would be at higher risk of SCD. However, when analysing the data from the trials that these recommendations are based on, the number of patients in whom an ICD delivers appropriate therapy is modest. In order to improve the effectiveness of therapy with an ICD, the patients who are most likely to benefit need to be identified. This review article presents the evidence behind current guideline-directed SCD risk markers and then explores new potential imaging, electrophysiological and genetic risk markers for SCD in DCM.

Abstract Objective - to determine whether patients with unexpected prehospital cardiac arrest could be identified in whom ambulance resuscitation attempts would be futile. Design - review of ambulance and hospital [...]

Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke.

Despite significant progress in cardiovascular pharmacotherapy and interventional strategies, cardiovascular disease (CVD), in particular ischaemic heart disease, remains the leading cause of morbidity and mortality among women in the UK and worldwide. Women are underdiagnosed, undertreated and under-represented in clinical trials directed at management strategies for CVD, making their results less applicable to this subset. Women have additional sex-specific risk factors that put them at higher risk of future cardiovascular events. Psychosocial risk factors, socioeconomic deprivation and environmental factors have an augmented impact on women’s cardiovascular health, highlighting the need for a holistic approach to care that considers risk factors specifically related to female biology alongside the traditional risk factors. Importantly, in the UK, even in the context of a National Health Service, there exist significant regional variations in age-standardised mortality rates among patients with CVD. Given most CVDs are preventable, concerted efforts are necessary to address the unmet needs and ensure parity of care for women with CVD. The present consensus document, put together by the British Cardiovascular Society (BCS)’s affiliated societies, specifically portrays the current status on the sex-related differences in the diagnosis and treatment of each of the major CVD areas and proposes strategies to overcome the barriers in accessing diagnoses and treatments among women. This document aims at raising awareness of the scale of the current problem and hopes to stimulate a multifaceted approach to address sex disparities and enable future comprehensive sex- and gender-based research through collaboration across different affiliated societies within the BCS.

Heart failure (HF) is emerging as a major public health problem both in high- and low - income countries. The mortality and morbidity due to HF is substantially higher in low-middle income countries (LMICs). Accessibility, availability and affordability issues affect the guideline directed therapy implementation in HF care in those countries. This call to action urges all those concerned to initiate preventive strategies as early as possible, so that we can reduce HF-related morbidity and mortality. The most important step is to have better prevention and treatment strategies for diseases such as hypertension, ischemic heart disease (IHD), type-2 diabetes, and rheumatic heart disease (RHD) which predispose to the development of HF. Setting up dedicated HF-clinics manned by HF Nurses, can help in streamlining HF care. Subsidized in-patient care, financial assistance for device therapy, use of generic medicines (including polypill strategy) will be helpful, along with the use of digital technologies.

ObjectivesTo investigate ethnic differences in susceptibility to bradycardias in South Asian and white European patients in the UK by determining rates of permanent pacemaker (PPM) implantation for sinus node dysfunction (SND) and atrioventricular block (AVB) in each ethnic group.MethodsWe carried out a retrospective cohort study into new PPM implantation during the period from 1 May 2006 to 31 March 2014, in patients of South Asian and Caucasian ethnicity resident in Leicestershire, UK. Numbers of individuals at risk in each ethnic group were derived from UK National Census data of 2011. Crude, and age-standardised incidence rates and risk ratios per 1000 population of PPM implantation were calculated for Caucasians and South Asians.ResultsDuring the study period, 4883 individuals from the Leicestershire population of 980 328 underwent PPM implantation, a cumulative implantation rate of 4.98/1000 population. The population cumulative PPM implantation rate for SND was 1.74/1000, AVB 2.83/1000 and other indications 0.38/1000 population. The crude incidence in Caucasians (6.15/1000 population) was higher than in South Asians (1.07/1000 population) and remained higher after age standardisation (5.60/1000 vs 2.03/1000, P<0.001). The age-standardised cumulative PPM implantation rates were lower in South Asians for both SND (0.53/1000 in South Asians; 1.97/1000 in Caucasians, P<0.001) and AVB (1.30/1000 in South Asians; 3.17/1000 in Caucasians, P<0.001). Standardised risk ratios (95% CI) for PPM implantation in South Asians compared with Caucasians for all pacing indications, SND and AVB were 0.36 (95% CI 0.36 to 0.37), 0.27 (95% CI 0.27 to 0.28) and 0.41 (95% CI 0.41 to 0.42), respectively.ConclusionsRates of PPM implantation are lower in South Asians residing in the UK, compared with Caucasians. This observation raises the possibility of lower inherent susceptibility to bradycardias in South Asians compared with Caucasians. Studies aimed at identifying underlying mechanisms, including possible genetic differences, are warranted.

Recent studies show sulfur redox processes in terrestrial settings are more important than previously considered, but much remains uncertain about how these processes respond to dynamic hydrologic conditions in natural field settings. We used field observations from a sulfate‐impacted wetland and stream in the mining region of Minnesota (USA) to calibrate a reactive transport model and evaluate sulfur and coupled geochemical processes under contrasting hydrogeochemical scenarios. Simulations of different hydrological conditions showed that flux and chemistry differences between surface water and deeper groundwater strongly control hyporheic zone geochemical profiles. However, model results for the stream channel versus wetlands indicate sediment organic carbon content to be the more important driver of sulfate reduction rates. A complex nonlinear relationship between sulfate reduction rates and geochemical conditions is apparent from the model's higher sensitivity to sulfate concentrations in settings with higher organic content. Across all scenarios, simulated e−balance results unexpectedly showed that sulfate reduction dominates iron reduction, which is contrary to the traditional thermodynamic ladder but corroborates recent experimental findings by Hansel et al. (2015) that “cryptic” sulfur cycling could drive sulfate reduction in preference over iron reduction. Following the thermodynamic ladder, our models shows that high surface water sulfate slows methanogenesis in shallow sediments, but field observations suggest that sulfate reduction may not entirely suppress methane. Overall, our results show that sulfate reduction may serve as a major component making up and influencing terrestrial redox processes, with dynamic hyporheic fluxes controlling sulfate concentrations and reaction rates, especially in high organic content settings. Unlike in oceans, sulfur reactions have not been considered to play a prominent role in the biogeochemistry of terrestrial environments because of much lower concentrations, but recent studies have been showing terrestrial sulfur reactions to be more important than previously thought. These reactions often take place in wetland, stream, and lake sediments, which can contain a mix of both surface water and underlying groundwater. Our study investigated how water fluxes through these sediments can affect sulfur reactions when the surface water and groundwater chemistry differ significantly, such as through influxes of surface water sulfur from mining activities. Using field measurements and a computer model that simulates chemical reactions and water flow, we found that water flux drives water chemistry in wetland and stream sediments. This affects how rapidly sulfur reactions occur, especially in organic‐rich wetland sediments. The model showed sulfur reactions to dominate over iron reactions, which contradicts classic chemical thermodynamics. Also, when water fluxes carry high sulfur concentrations into wetland sediments, sulfur reactions out compete production of methane, a strong greenhouse gas. Our results indicate that sulfur reactions can play a prominent role in terrestrial biogeochemistry, and the degree to which it does is affected by hydrological fluxes. Dynamic water fluxes affect sulfate reduction rates in hyporheic zones, especially where organic content is highField data and reactive transport modeling suggest sulfate reduction can dominate Fe reduction in stream and wetland sedimentsHigh sulfate concentrations slow methanogenesis in wetlands but do not entirely suppress methane

Tumor necrosis factor-α (TNF-α)-induced RIP1/RIP3 (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3)-mediated necroptosis has been proposed as an alternative strategy for treating apoptosis-resistant leukemia. However, we found that most acute myeloid leukemia (AML) cells, especially M4 and M5 subtypes, produce TNF and show basal level activation of RIP1/RIP3/MLKL signaling, yet do not undergo necroptosis. TNF, through RIP1/RIP3 signaling, prevents degradation of SOCS1, a key negative regulator of interferon-γ (IFN-γ) signaling. Using both pharmacologic and genetic assays, we show here that inactivation of RIP1/RIP3 resulted in reduction of SOCS1 protein levels and partial differentiation of AML cells. AML cells with inactivated RIP1/RIP3 signaling show increased sensitivity to IFN-γ-induced differentiation. RIP1/RIP3 inactivation combined with IFN-γ treatment significantly attenuated the clonogenic capacity of both primary AML cells and AML cell lines. This combination treatment also compromised the leukemogenic ability of murine AML cells in vivo. Our studies suggest that inhibition of RIP1/RIP3-mediated necroptotic signaling might be a novel strategy for the treatment of AML when combined with other differentiation inducers.

MUC1 is a cell membrane-associated mucin, expressed ubiquitously on the mucosal epithelia as well as by immune cells, that limits the inflammatory response to multiple pathogens. We have recently shown that MUC1 controls inflammation resulting from Helicobacter pyloriinfection by suppressing interleukin-1ß (IL-1ß) produced via the NLRP3 inflammasome. Here, we demonstrate that MUC1 also regulates IL-1ß secretion induced by the NLRP3-activating bacteria Haemophilus influenzaebut not bacteria that activate other inflammasomes. Using purified ligands, we further demonstrate that MUC1 regulation of NLRP3 is specific, as it has no effect on the NLRP1b, NLRC4 and AIM2 inflammasomes. This indicates a unique role for MUC1 in the regulation of NLRP3-activating bacterial infections.

Objective:Material testing system is a conventional but destructive method for measuring the biomechanical properties of wound tissues in basic research. The recently developed optical coherence tomography-based air-jet indentation system is a non-destructive method for measuring these properties of soft tissues in a non-contact manner. The aim of the study was to examine the correlation between the biomechanical properties of wound tissues measured by the two systems.Method:Young male Sprague-Dawley rats with streptozotocin-induced diabetic were wounded by a 6 mm biopsy punch on their hind limbs. The biomechanical properties of wound tissues were assessed with the two systems on post-wounding days 3, 7, 10, 14, and 21. Wound sections were stained with picro-sirius red for analysis on the collagen fibres. Data obtained on the different days were charted to obtain the change in biomechanical properties across the time points, and then pooled to examine the correlation between measurements made by the two devices. Qualitative analysis to determine any correlation between indentation stiffness measured by the air-jet indentation system and the orientation of collagen fibres.Results:The indentation stiffness is significantly negatively correlated to the maximum load, maximum tensile stress, and Young's modulus by the material testing system (all p<0.05). The orientation of collagen changes with the indentation stiffness over time.Conclusion:Our findings support the use of optical coherence tomography-based air-jet indentation system to evaluate the biomechanical properties of wounds in a non-contact manner. It is a potential clinical device to examine the biomechanical properties of chronic wounds in vivoin a repeatable manner.

Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension.

To investigate the mechanisms for the previously reported development of adult cardiac hypertrophy in male rats following growth restriction, the levels of oxidative stress and activation of signaling kinases were measured in the left ventricle (LV) of adult rat offspring. In experiment one, bilateral uterine vessel ligation to induce uteroplacental insufficiency and growth restriction in the offspring (Restricted) or sham surgery was performed during pregnancy. Litters from sham mothers had litter size either reduced (Reduced Litter), which also restricted postnatal growth, or were left unaltered (Control). In males, Reduced Litter offspring had increased LV phosphorylation of AMPKa, p38 MAPK and Akt compared with Restricted and Controls (P< 0.05). In females, both Restricted and Reduced Litter adult offspring had increased LV phosphorylation of p38 MAPK and Akt, however, only Restricted offspring had increased phosphorylation of AMPKa (P< 0.05). In addition, only Restricted male offspring displayed LV oxidative stress (P< 0.05). Experiment two investigated in mothers exposed to uteroplacental insufficiency or sham surgery the effects of cross-fostering offspring at birth, and therefore the effects of the postnatal lactational environment. Surprisingly, the cross-fostering itself resulted in increased LV phosphorylation of AMPKa and Akt in females and increased phosphorylation of Akt in males compared with Control non-cross-fostered offspring (P< 0.05). In conclusion, kinase signaling in the adult LV can be programmed by uteroplacental insufficiency induced growth restriction in a gender-specific manner. In addition, the heart of adult rats is also sensitive to programming following the postnatal intervention of cross-fostering alone as well as by postnatal growth restriction.

Some recent research in laser-induced surface ripple structures, surface ablation, surface colouration, and their potential industrial applications are discussed in this article. Both wavelength and sub-wavelength periodic surface structures were observed on semiconductors such as InP and GaN/sapphire surfaces after irradiation of femtosecond laser pulses. The orientation of the periodic structures was dependant on the laser beam polarization, and the period was dependent on the incident laser fluence. Such surface periodic structures may find applications in controlling surface hydrophobic and hydrophilic properties. Excimer laser ablation of epoxy compounds from wafer level chip size packages was found to be a feasible method to expose the micron-size Au bumps for solder reflow, which is a critical process in manufacturing portable electronic products. Studies on controlled surface oxidation by laser pulses showed that a range of colours can be achieved on a stainless steel surface. Selective Cr oxidation and iron oxides were detected. The appearance of colour is the result of the light constructive interference of the transparent oxide layer and is determined by the oxide thickness and the refractive index. The potential industrial applications of the techniques are discussed.

Aims:The Reveal® Plus implantable loop recorder offers additional automatic detection of arrhythmias that may not be symptomatic. We evaluated the clinical utility of this function compared with standard patient activation. Methods:Over an 18 month period, 50 consecutive patients (age 54 ± 20 years; 24 male) with unexplained dizziness, palpitations and/or syncope had ILR activations which were downloaded for analysis. Patient and auto-activation were analysed with respect to arrhythmia detection and the impact on management of patients was examined. Results:Patient symptoms were syncope in 72% and non-syncope (dizziness and/or palpitations) in 28%. There were 181 patient activation events with 16% showing symptomatic arrhythmia leading to a positive diagnosis in 8 patients. Of 682 auto-activations, detection was appropriate in 17% and inappropriate in 83% (undersensing in 76% and oversensing in 24%). In 8 patients clinically relevant arrhythmia was detected by patient activation alone. In 4 of these patients, further arrhythmia was detected by auto-activation. No patient had important arrhythmia detected only by auto-activation. Conclusion:Automatic detection of asymptomatic arrhythmia did not appear to improve the diagnostic utility of the ILR in our series. The large number of stored inappropriate auto-activation events limits the ability of this function to detect clinically relevant arrhythmia. Symptom-rhythm correlation using the patient activation function remains clinically useful in patients with unexplained syncope or palpitation.

Background:Electrophysiological study (EPS) followed by radiofrequency (RF) ablation has emerged as the treatment of choice for symptomatic narrow complex tachycardia (NCT), for which purpose, 5 catheters are typically used (4 for the initial EPS and an additional one for the subsequent RF ablation). We describe an alternative, streamlined approach using only 3 catheters [2 standard (diagnostic) and 1 deflectable, thermistor tip (mapping)] as the standard configuration for EPS and RF ablation in patients with NCT but no pre-excitation on ECG. Methods and Results:Diagnosis was obtained in all 250 consecutive patients (mean age 45 years, 174 females): atrio-ventricular nodal re-entrant tachycardia (AVNRT) in 188 (75%), concealed accessory pathways (AP's) in 38 patients (15%), ectopic atrial tachycardia in 19 patients (8%), persistent junctional re-entrant tachycardia (PJRT) in 4 patients (2%) and atrial fibrillation in 1 patient. An additional diagnostic catheter was used for optimising atrial pacing in 3 patients and for ventricular pacing in concealed right postero-septal AP's in another 3. An additional mapping catheter was used in 31 patients with concealed left-sided AP's, 2 with multiple AP's and 1 with PJRT. Three patients had complications (1 pulmonary embolism, 1 pericardial effusion and 1 atrio-ventricular node block). Overall, the immediate success rate was 98% (224/229) with a recurrence rate of 4.4% (10/224), and the total success rate (with repeat RF ablation if necessary) was 99.2% (227/229) over a median follow-up period of 31.4 months. The average cost saving was US$474 per procedure. Procedure duration (2.0 ± 0.1 hours), fluoroscopy time (13 ± 1 minutes) and the number of radiofrequency applications (5.4 ± 0.3) also compared favourably with values reported in the literature for RF ablation of AVNRT. Conclusion:Compared to the conventional 5-catheter configuration for the combined EPS and RF ablation procedure in treatment of patients with NCT, the described 3-catheter configuration reduces cost, procedure duration and fluoroscopy time without compromising on success rate and safety. On these bases, we advocate its widespread adoption.

Randomized clinical trials play an increasingly important role in guiding management decisions, and survival curves are the most popular means for summarizing and depicting the results of a clinical trial. However, survival curves may create certain “visual illusions” that can be misinterpreted by the unwary, with potentially adverse effects on patient care. The authors provide a brief outline of the theoretical background of survival curves and explain the origin of the most common visual illusions. Statisticians need to be aware of such potential for misinterpretation of clinical trial data in order to safeguard clinicians against drawing undue inferences and applying them to actual practice.

Cardiac parasympathetic control has prognostic significance in heart failure, but the control mechanisms of this system remain poorly defined. We have demonstrated previously a facilitatory role for nitric oxide (NO) in the parasympathetic control of heart rate in young healthy human subjects. In view of the complex abnormalities of regional NO activity observed in chronic heart failure, we now aim to establish if this mechanism is active in subjects with this condition. Groups of 12heart failure patients [NYHA class II-III; mean age 52 years (range 38-67 years)] and 12 age/sex-matched healthy control subjects [mean age 50 years (range 36-62 years)] were studied. Heart rate variability and baroreflex sensitivity were measured during inhibition of endogenous NO production with NG-monomethyl-l-arginine (l-NMMA; 3mgċh-1ċkg-1) and during administration of an equipressor dose of the control vasoconstrictor phenylephrine (12-36μgċh-1ċkg-1). Basal levels of nitrate+nitrite were measured in the plasma as an indication of systemic NO production. In the heart failure patients, despite an equal rise in blood pressure with both drugs, high-frequency indices of heart rate variability increased less with l-NMMA than with phenylephrine: RMSSD (root mean square of successive RR-interval differences) increased by 4±2 compared with 26±8ms (P < 0.001) and high-frequency power increased by 97±62 compared with 1372±861ms2 (P < 0.001). The increases in cross-spectral baroreflex sensitivity were also lower with l-NMMA than with phenylephrine [high-frequency α-index, 2.2±1.3 and 12.6±3.8ms/mmHg respectively (P < 0.001); low-frequency α-index, 1.3±0.9 and 4.3±1.7ms/mmHg respectively (P < 0.05)]. Healthy subjects showed a similar discrepancy in the response of high-frequency indices of heart rate variability to the two drugs, although baroreflex sensitivity responses were significantly different only for the high-frequency α-index. Levels of plasma nitrate+nitrite were significantly higher in the heart failure patients compared with controls. These data demonstrate that baroreflex-mediated cardiac parasympathetic activation in human heart failure, as in health, is dependent upon endogenous NO synthesis.

Binary and continuous phase-only surface relief diffractive optical elements can be fabricated on hybrid sol-gel glass based on a single-step microfabrication process. We report on the fabrication and characterization of an inorganic-organic hybrid SiO2/TiO2sol-gel glass by UV light exposure. Preliminary results of binary and continuous surface relief structures fabricated on sol-gel glass with UV exposure using holographic technique and a high-energy-beam-sensitive (HEBS) glass mask are demonstrated. The effects of the fabrication parameters such as doping concentration, bake temperature, and UV light exposure time on the film characteristics (thickness and refractive index) are studied. © 2001 Society of Photo-Optical Instrumentation Engineers.

Gabapentin (Neurontin, Pfizer Global R & D) is a novel anticonvulsant, antihyperalgesic, and antinociceptive agent with a poorly understood mechanism of action. In this study, we show that gabapentin (EC50 2 microM) inhibited up to 70 to 80% of the total K+-evoked Ca2+ influx via voltage-dependent calcium channels (VD-CCs) in a mouse pituitary intermediate melanotrope clonal mIL-tsA58 (mIL) cell line. mIL cells endogenously express only gamma-aminobutyric acid type B (GABA(B)) gb1a-gb2 receptors. Moreover, activity of the agonist gabapentin was dose dependently and completely blocked with the GABA(B) antagonist CGP55845 and was nearly identical to the prototypic GABA(B) agonist baclofen in both extent and potency. Antisense knockdown of gb1a also completely blocked gabapentin activity, while gb1b antisense and control oligonucleotides had no effect, indicating that gabapentin inhibition of membrane Ca2+ mobilization in mIL cells was dependent on a functional GABA(B) (gb1a-gb2) heterodimer receptor. In addition, during combined whole cell recording and multiphoton Ca2+ imaging in hippocampal neurons in situ, gabapentin significantly inhibited in a dose-dependent manner subthreshold soma depolarizations and Ca2+ responses evoked by somatic current injection. Furthermore, gabapentin almost completely blocked Ca2+ action potentials and Ca2+ responses elicited by suprathreshold current injection. However, larger current injection overcame this inhibition of Ca2+ action potentials suggesting that gabapentin did not predominantly affect L-type Ca2+ channels. The depressant effect of gabapentin on Ca2+ responses was coupled to the activation of neuronal GABA(B) receptors since they were blocked by CGP55845, and baclofen produced similar effects. Thus gabapentin activation of neuronal GABA(B) gb1a-gb2 receptors negatively coupled to VD-CCs can be a potentially important therapeutic mechanism of action of gabapentin that may be linked to inhibition of neurotransmitter release in some systems.

Abstract. A recently described cytotoxic monoclonal antibody (mAb 1D5) raised against Blastocystis hominis isolate B, was tested for reactivity with 13 different isolates of Blastocystis. The isolates used were previously isolated from humans, rats and reptiles and were maintained as axenised cultures throughout the course of this study. Five B. hominis isolates (B, C, E, G and H) were found to react with mAb 1D5 in immunoblotting studies and the indirect fluorescence antibody test. The pattern of fluorescence observed for all five isolates was diffuse and patchy. Immunoblotting studies revealed that mAb 1D5 reacted with a 29-30-kDa protein found in all five isolates. Results of a cytotoxic assay showed that the mAb exhibited a complement-independent cytotoxic effect on all the exposed isolates. Microscopic observations showed differences in morphology between the Blastocystis cells exposed and unexposed to mAb. Acridine orange staining performed on both exposed and unexposed cells showed similar internal structures when viewed under fluorescence microscopy.

A novel isolated Langendorff perfused rabbit heart preparation with intact dual autonomic innervation is described. This preparation allows the study of the effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart. These hearts (n = 10) had baseline heart rates of 146 ± 2 beats min-1 which could be increased to 240 ±11 beats min-1 by sympathetic stimulation (15 Hz) and decreased to 74 ± 11 beats min-1 by stimulation of the vagus nerve (right vagus, 7 Hz). This model has the advantage of isolated preparations, with the absence of influence from circulating hormones and haemodynamic reflexes, and also that of in vivo preparations where direct nerve stimulation is possible without the need to use pharmacological agents. Data are presented characterising the preparation with respect to the effects of autonomic nerve stimulation on intrinsic heart rate and atrioventricular conduction at different stimulation frequencies. We show that stimulation of the right and left vagus nerve have differential effects on heart rate and atrioventricular conduction. Experimental Physiology (2001) 86.3, 319-329.

Background: Irregular broad complex tachycardia (BCT) may be due to atrial fibrillation (AF) occurring in the presence of ventricular pre‐excitation (pre‐excited AF) or bundle branch block (BBB‐AF). While irregularity is a defining characteristic of AF. it is a common subjective impression that greater variability in manifestation exists for pre‐excited AF than BBB‐AF. This difference can potentially be exploited for distinguishing the two conditions it some means can be found to quantify it.

Gamma-aminobutyric acid (GABA) activates two qualitatively different inhibitory mechanisms through ionotropic GABA(A) multisubunit chloride channel receptors and metabotropic GABA(B) G protein-coupled receptors. Evidence suggests that pharmacologically distinct GABA(B) receptor subtypes mediate presynaptic inhibition of neurotransmitter release by reducing Ca2+ conductance, and postsynaptic inhibition of neuronal excitability by activating inwardly rectifying K+ (Kir) conductance. However, the cloning of GABA(B) gb1 and gb2 receptor genes and identification of the functional GABA(B) gb1-gb2 receptor heterodimer have so far failed to substantiate the existence of pharmacologically distinct receptor subtypes. The anticonvulsant, antihyperalgesic, and anxiolytic agent gabapentin (Neurontin) is a 3-alkylated GABA analog with an unknown mechanism of action. Here we report that gabapentin is an agonist at the GABA(B) gb1a-gb2 heterodimer coupled to Kir 3.1/3.2 inwardly rectifying K+ channels in Xenopus laevis oocytes. Gabapentin was practically inactive at the human gb1b-gb2 heterodimer, a novel human gb1c-gb2 heterodimer and did not block GABA agonism at these heterodimer subtypes. Gabapentin was not an agonist at recombinant GABA(A) receptors as well. In CA1 pyramidal neurons of rat hippocampal slices, gabapentin activated postsynaptic K+ currents, probably via the gb1a-gb2 heterodimer coupled to inward rectifiers, but did not presynaptically depress monosynaptic GABA(A) inhibitory postsynaptic currents. Gabapentin is the first GABA(B) receptor subtype-selective agonist identified providing proof of pharmacologically and physiologically distinct receptor subtypes. This selective agonism of postsynaptic GABA(B) receptor subtypes by gabapentin in hippocampal neurons may be its key therapeutic advantage as an anticonvulsant.

Tan, K. S. W., Ng, G. C., Quek, E., Howe, J., Ramachandran, N. P., Yap, E. H., and Singh, M. 2000. Blastocystis hominis: A simplified, high-efficiency method for clonal growth on solid agar. Experimental Parasitology96, 9–15. Colony growth of protozoan parasites in agar can be useful for axenization, cloning, and viability studies. This is usually achieved with the pour plate method, for which the parasite colonies are situated within the agar. This technique has been described for Giardia intestinalis, Trichomonas vaginalis, and Entamoeba and Blastocystis species. Extracting such colonies can be laborious. It would be especially useful if parasites could be grown on agar as colonies. These colonies, being exposed on the agar surface, could be conveniently isolated for further investigation. In this study, we report the successful culture of B. hominis cells as colonies on solid agar. Colonies were enumerated and the efficiency of plating was determined. It was observed that B. hominis could be easily cultured on agar as clones. The colonies were dome-shaped and mucoid and could grow to 3 mm in diameter. Flow cytometric analyses revealed that parasite colonies remained viable for up to 2 weeks. Viable colonies were conveniently expanded in liquid or solid media. Scanning electron microscopy revealed that each colony consists of two regions; a dome-shaped, central core region and a flattened, peripheral region. Older colonies possessed numerous strand-like surface coat projections. This study provides the first report of clonal growth of B. hominis on agar and a simple, effective method for cloning and expansion of B. hominis cells.

Selective regrowth, which involves the growth of a device structure, patterning, etching and epitaxial regrowth of another device structure is an important technique for monolithic integration. The nature of the surface before the regrowth is crucial for realizing good quality regrown devices. In this study, the effect of different GaAs surface preparation processes on the electrical and optical characteristics of a regrown pseudomorphic high electron mobility transistor (PHEMT) is studied. Using photoluminescence, Hall, atomic force microscopy and d.c. and microwave measurements on devices, an optimized process sequence has been identified to fabricate PHEMT structures with equivalent characteristics of those grown on epiready wafers.

Numerous mutant G protein-coupled receptors with diminished or no function have been described that are naturally occurring or that are the product of gene manipulation. It has largely been assumed that receptor mutants do not affect the function of the wild-type receptor; however, the occurrence of G protein-coupled receptor dimerization suggests the possibility that an intermolecular interaction between mutant and wild-type receptors can occur. We have shown previously that the D2 dopamine receptor (D2DR) exists as dimers in cell lines and brain tissue. In this study, we demonstrated that mutant D2DR can modulate the function of the wild-type D2DR. While attempting to elucidate the structure of the D2DR dimer, we demonstrated that nonfunctional D2DR substitution and truncation mutants antagonized wild-type D2DR function. Furthermore, from analyses of this interaction between the receptor mutants and the D2DR, using photoaffinity labeling, we provide evidence that the D2DR is oligomeric in the cell.

Direct evidence is lacking to show whether the gamma-aminobutyric acid (GABA)(B) gb1-gb2 heterodimer is the signaling form of the receptor. In this study, we tested whether gb1a or gb2 subunits when coexpressed with truncated receptors or metabotropic glutamate receptor mGluR4 could form functional GABA receptors. Coexpression of the ligand binding N-terminal domain of gb1a or the C-terminal portion of gb1a composing the seven-transmembrane segments and intracellular loops with gb2 could not reconstitute functional receptors. We next examined whether mGluR4, which forms homodimers and is structurally related to GABA(B), could act as a surrogate coreceptor for gb1 or gb2. The coexpression of mGluR4 and gb1a led to the expression of gb1a monomers on cell surface membranes as determined by immunoblot analysis and flow cytometry. However, mGluR4-gb1a heterodimers were not formed, and membrane-expressed gb1a monomers were not functionally coupled to adenylyl cyclase in human embryonic kidney 293 cells or activated inwardly rectifying potassium (Kir) channels in Xenopus oocytes. Similarly, the coexpression of mGluR4 and gb2 led to nonfunctional GABA receptors. GABA-activated distal signaling events resulted only after the coexpression and heterodimerization of gb1 and gb2. Taken together with the truncated receptor studies, the data suggest that a high degree of structural specificity is required to form the functional GABA(B) receptor that is a gb1-gb2 heterodimer.

G protein-coupled receptors are commonly thought to bind their cognate ligands and elicit functional responses primarily as monomeric receptors. In studying the recombinant gamma-aminobutyric acid, type B (GABAB) receptor (gb1a) and a GABAB-like orphan receptor (gb2), we observed that both receptors are functionally inactive when expressed individually in multiple heterologous systems. Characterization of the tissue distribution of each of the receptors by in situ hybridization histochemistry in rat brain revealed co-localization of gb1 and gb2 transcripts in many brain regions, suggesting the hypothesis that gb1 and gb2 may interact in vivo. In three established functional systems (inwardly rectifying K+ channel currents in Xenopus oocytes, melanophore pigment aggregation, and direct cAMP measurements in HEK-293 cells), GABA mediated a functional response in cells coexpressing gb1a and gb2 but not in cells expressing either receptor individually. This GABA activity could be blocked with the GABAB receptor antagonist CGP71872. In COS-7 cells coexpressing gb1a and gb2 receptors, co-immunoprecipitation of gb1a and gb2 receptors was demonstrated, indicating that gb1a and gb2 act as subunits in the formation of a functional GABAB receptor.

A c-myc epitope-tagged human dopamine D1 receptor (c-myc D1 receptor) was expressed in Sf9 cells and its cellular distribution under basal conditions and after exposure to the agonist dopamine was examined. In the basal state, immunofluorescently labeled c-myc D1 receptors imaged by confocal microscopy appeared as a bright ring of label predominantly on the cell surface, and to a lesser extent as intracellular clusters of label. This pattern of receptor distribution was confirmed by radioligand-binding assays on plasma membrane and light membrane fractions using the D1 receptor-antagonist [3H]-SCH-23390. After exposure to dopamine, c-myc D1 receptors were redistributed on the cell surface, changing from a continuous ring to a discontinuous pattern of label. Analysis of fluorescence intensity and three-dimensional computer reconstruction of labeled receptors revealed a 30% decrease in surface labeling with no decrease in total number of receptors confirmed by radioligand-binding analysis. These findings constituted the first direct evidence of agonist-induced D1 receptor internalization. The results showed that the combination of confocal microscopy and three-dimensional reconstruction can be used to visualize and assess receptor distribution in Sf9 cells.

Using inbred strains of mice that differ widely in their innate preference for and consumption of ethanol, we demonstrate, in ethanol-preferring C57BL/6J (C57) mice, decreased dopamine (DA) content and turnover in the terminals of the mesolimbic and mesostriatal dopamine neurons, compared with ethanol-avoiding DBA/2J and BALBc mice. These data suggest that genetically determined hypodopaminergic function in these pathways plays a role in the predisposition to high voluntary intake of ethanol. DA turnover in these areas was selectively increased by ethanol in C57 mice, which suggests that these DA neurons are among the central substrates of ethanol action in brain. In keeping with this hypothesis, augmenting synaptic DA concentrations by enhancing the synthesis by L-3-4-dihydroxyphenylalanine with carbidopa, or by decreasing its degradation by monoamine oxidase-B blockade with selegiline, led to marked decreases in ethanol preference and in the high voluntary consumption of ethanol in C57 mice. The selegiline-mediated decrease in ethanol preference and drinking in C57 mice could be blocked selectively by D1 and D2 DA receptor antagonists, which suggests that DA activity at D1 and D2 receptors plays an important role in this behavior. Indeed, the high preference for ethanol in C57 animals could be attenuated by direct DA receptor activation by either D1 or D2 agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

In this paper, we present two on‐line adaptive control algorithms for non‐linear plants using neural networks. The architecture used is based on the concept of specialized learning, which was first proposed by Psaltis et al.and suffers from two main problems, namely lack of knowledge of the plant Jacobian and slow training speed if the standard backpropagation algorithm is used. Specialized learning has been tested successfully by several researchers using the sign of the plant Jacobian, chosen on the basis of prior qualitative knowledge of the plant. It has also been proposed to calculate the plant Jacobian through a pretrained model. However, if off‐line training of the model is not possible and qualitative knowledge of the plant Jacobian is not available, then specialised learning may not be feasible foran on‐line neurocontroller. We propose that it is possible to estimate the plant Jacobian through the model on‐line for a slowly varying plant. Some analysis for calculating the plant Jacobian on‐line is discussed. For rapidly varying plant, we propose using the recursive least‐squares (RLS) training algorithm instead of the standard back‐propagation (BP) algorithm in the specialised learning architecture. We show that RLS training is faster than the BP algorithm. The proposed fast algorithm is then tested on simulated non‐linear plants as well as in a real‐time application to a coupled‐tanks test rig. © 1998 John Wiley & Sons, Ltd.

Abstract:  The growth of axenic reptilian isolates of Blastocystis in Iscove’s modified Dulbecco’s medium (IMDM) was studied and the morphology of the parasite was examined by phase-contrast microscopy. The chromosomal patterns of these reptilian isolates of Blastocystis were examined by pulsed-field gel electrophoresis (PFGE) and compared with those of B. hominis and B. lapemi, a sea snake Blastocystis. IMDM with 10% horse serum supported excellent growth of the reptilian Blastocystis isolates. The parasites from all the isolates were predominantly vacuolar, but multivacuolar and amoeboid forms were also seen. Amoeboid forms with rather elongate pseudopodia were also observed. There were some differences in size, morphology, and growth characteristics in the different reptilian isolates. The karyotypic patterns of the Blastocystis isolates from tortoise, iguana, and python were distinctly different from one another and from those obtained with B. hominis and B. lapemi. On the basis of the above-mentioned differences in chromosomal patterns, the tortoise, iguana, and python isolates are described as new species, viz., B. geocheloni sp. nov. from Geochelone carbonaria (red-footed tortoise), B. cycluri sp. nov. from Cyclura cornuta (rhino iguana), and B. pythoni sp. nov. from Python reticulatus (reticulated python).