Levels of adenosine deaminase in some experimental animal tumours and the possible therapeutic effect of the ADA inhibitor 2-deoxy-coformycin.

The intracellular adenosine deaminase activities (ADA) in 12 different experimental animal tumours were measured. Unlike the leukaemic lymphoblasts of man, those of two spontaneous rat leukaemias did not have elevated levels of the enzyme. Very high levels were found in a rat plasma-cell tumour (IR 461) and an attempt was made to treat such tumours with the specific enzyme inhibitor, 2-deoxy-coformycin. The shortage of this drug prevented a systematic study, but a daily dose of 8 mg/kg had a significant inhibitory effect on the growth of tumours

Automatic Detection of Cortical Arousals in Sleep and their Contribution to Daytime Sleepiness

Cortical arousals are transient events of disturbed sleep that occur spontaneously or in response to stimuli such as apneic events. The gold standard for arousal detection in human polysomnographic recordings (PSGs) is manual annotation by expert human scorers, a method with significant interscorer variability. In this study, we developed an automated method, the Multimodal Arousal Detector (MAD), to detect arousals using deep learning methods. The MAD was trained on 2,889 PSGs to detect both cortical arousals and wakefulness in 1 second intervals. Furthermore, the relationship between MAD-predicted labels on PSGs and next day mean sleep latency (MSL) on a multiple sleep latency test (MSLT), a reflection of daytime sleepiness, was analyzed in 1447 MSLT instances in 873 subjects. In a dataset of 1,026 PSGs, the MAD achieved a F1 score of 0.76 for arousal detection, while wakefulness was predicted with an accuracy of 0.95. In 60 PSGs scored by multiple human expert technicians, the MAD significantly outperformed the average human scorer for arousal detection with a difference in F1 score of 0.09. After controlling for other known covariates, a doubling of the arousal index was associated with an average decrease in MSL of 40 seconds ($\beta$ = -0.67, p = 0.0075). The MAD outperformed the average human expert and the MAD-predicted arousals were shown to be significant predictors of MSL, which demonstrate clinical validity the MAD.Comment: 40 pages, 13 figures, 9 table

Inter-expert and intra-expert reliability in sleep spindle scoring

Objectives: To measure the inter-expert and intra-expert agreement in sleep spindle scoring, and to quantify how many experts are needed to build a reliable dataset of sleep spindle scorings. Methods: The EEG dataset was comprised of 400 randomly selected 115 s segments of stage 2 sleep from 110 sleeping subjects in the general population (57 ± 8, range: 42–72 years). To assess expert agreement, a total of 24 Registered Polysomnographic Technologists (RPSGTs) scored spindles in a subset of the EEG dataset at a single electrode location (C3-M2). Intra-expert and inter-expert agreements were calculated as F_1-scores, Cohen’s kappa (κ), and intra-class correlation coefficient (ICC). Results: We found an average intra-expert F_1-score agreement of 72 ± 7% (κ: 0.66 ± 0.07). The average inter-expert agreement was 61 ± 6% (κ: 0.52 ± 0.07). Amplitude and frequency of discrete spindles were calculated with higher reliability than the estimation of spindle duration. Reliability of sleep spindle scoring can be improved by using qualitative confidence scores, rather than a dichotomous yes/no scoring system. Conclusions: We estimate that 2–3 experts are needed to build a spindle scoring dataset with ‘substantial’ reliability (κ: 0.61–0.8), and 4 or more experts are needed to build a dataset with ‘almost perfect’ reliability (κ: 0.81–1). Significance: Spindle scoring is a critical part of sleep staging, and spindles are believed to play an important role in development, aging, and diseases of the nervous system

Balance control systems in Parkinson's disease and the impact of pedunculopontine area stimulation

Impaired balance is a major contributor to falls and diminished quality of life in Parkinson’s disease, yet the pathophysiology is poorly understood. Here, we assessed if patients with Parkinson’s disease and severe clinical balance impairment have deficits in the intermittent and continuous control systems proposed to maintain upright stance, and furthermore, whether such deficits are potentially reversible, with the experimental therapy of pedunculopontine nucleus deep brain stimulation. Two subject groups were assessed: (i) 13 patients with Parkinson’s disease and severe clinical balance impairment, implanted with pedunculopontine nucleus deep brain stimulators; and (ii) 13 healthy control subjects. Patients were assessed in the OFF medication state and blinded to two conditions; off and on pedunculopontine nucleus stimulation. Postural sway data (deviations in centre of pressure) were collected during quiet stance using posturography. Intermittent control of sway was assessed by calculating the frequency of intermittent switching behaviour (discontinuities), derived using a wavelet-based transformation of the sway time series. Continuous control of sway was assessed with a proportional–integral–derivative (PID) controller model using ballistic reaction time as a measure of feedback delay. Clinical balance impairment was assessed using the ‘pull test’ to rate postural reflexes and by rating attempts to arise from sitting to standing. Patients with Parkinson’s disease demonstrated reduced intermittent switching of postural sway compared with healthy controls. Patients also had abnormal feedback gains in postural sway according to the PID model. Pedunculopontine nucleus stimulation improved intermittent switching of postural sway, feedback gains in the PID model and clinical balance impairment. Clinical balance impairment correlated with intermittent switching of postural sway (rho = − 0.705, P < 0.001) and feedback gains in the PID model (rho = 0.619, P = 0.011). These results suggest that dysfunctional intermittent and continuous control systems may contribute to the pathophysiology of clinical balance impairment in Parkinson’s disease. Clinical balance impairment and their related control system deficits are potentially reversible, as demonstrated by their improvement with pedunculopontine nucleus deep brain stimulation

Wireless Network Virtualization: Opportunities for Sharing in the 3.5 GHz Band

In this paper, we evaluate the opportunities that Wireless Network Virtualization (WNV) can bring for spectrum sharing by focusing on the regulatory framework that has been deployed by the Federal Communications Commission (FCC) for the 3.5GHz band. Pairing this regulatory approach with WNV permits us to present a sharing proposal where emphasis is made on increasing resource availability and providing flexible methods for negotiating for resource access. We include an economics framework that aims at presenting an additional perspective on the attainable outcomes of our sharing proposal. We find that by pairing regulatory flexibility with an enabling technology, within an appropriate economics context, we can increase resource access opportunities and enhance current sharing arrangements

Progress in customer relationship management adoption: a cross-sector study

Although customer relationship management (CRM) is widely used by organizations to capture and manage customer data, the process of implementation can be problematic. This article takes a multi-sector view of CRM implementation in three areas of the UK services sector: banking and finance; professional services; and the government/public sector. The study captures variations in CRM practice and implementation across these sectors, applying an existing framework of CRM implementation to tease out progress in relation to people (the company's staff), the company itself, the customers, and the technology. The implications for organizations that have reached different implementation stages in their CRM journey are considered

Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata

C1 - Journal Articles RefereedAIMS: Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses. METHODS AND RESULTS: In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ∼50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ∼25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO(2)-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity. CONCLUSION: These data confirm a fundamental physiological role of medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO(2)

Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms

BACKGROUND: The increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the β2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent. METHODS: We investigated a group of 429 patients (55 ± 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 ± 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 ± 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the β2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes. RESULTS: Multivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The β2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023). CONCLUSION: Our study showed no significant modifying effect of the functionally relevant β2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile