‘Let’s regain our grip on things’: metaphysics and the ordinary in DeLillo and Wittgenstein

This thesis is a reading of five Don DeLillo novels in relation to the later philosophy of Ludwig Wittgenstein, beginning with Falling Man, and working backwards to The Names. It is an attempt to think about the philosophical aspects of DeLillo’s work; in particular, the various ways in which it is engaged with the possibility of metaphysics and its relation to the ordinary. It examines the ambiguous status of metaphysics, and the nature of transcendence and the ordinary in his fiction, arguing that they form a dialectical relation, which guides, structures and informs many of the pressing spiritual, existential, aesthetic, ontological and epistemological concerns of his writing. This dialectic is illuminated by a parallel dialectic at work in Wittgenstein’s philosophy. Wittgenstein’s thought is useful for a number of reasons: it is a method or style of seeing rather than a systematic, substantive theory; though critical of metaphysics it is profoundly engaged with the inescapability of the metaphysical impulse, and the way metaphysical problems seem embedded in everyday language; and it is committed to the ordinary, but not in any reductive sense – it is not a defence of common sense or conventional beliefs. Understanding DeLillo’s engagement with metaphysics as part of a dialectic with the ordinary, and viewing it through an encounter with Wittgenstein, will prevent recourse to traditionalist conceptions of language and meaning while at the same time resisting and critiquing the postmodern scepticism frequently invoked in DeLillo criticism. The thesis consists of a series of comparative readings that aim to further our understanding of DeLillo’s novels and Wittgenstein’s philosophy; readings centred around a set of closely related concerns that reflect different aspects of the dialectic between the ordinary and the transcendent: the paradox of the ordinary; the limits of language; looking at the overlooked; spiritual yearning; and the logical sublime

Wearable Neuromodulators

In neuromodulation, by delivering a form of stimulus to neural tissue the response of an associated neural circuit may be changed, enhanced or inhibited (i.e., modulated) as desired. This powerful technique may be used to treat various medical conditions as outlined in this chapter. After a brief introduction to the human nervous system, key example applications of electrical neuromodulation such as cardiac pacemakers, devices for pain relief, deep brain stimulation, cochlear implant and visual prosthesis and their respective methods of deployment are discussed. Furthermore, key features of wearable neuromodulators with reference to some existing devices are briefly reviewed. This chapter is concluded by a case study on design and development of a wearable device with non-invasive electrodes for treating lower urinary tract dysfunctions after spinal cord injury

Minimizing Stimulus Current in a Wearable Pudendal Nerve Stimulator Using Computational Models.

After spinal cord injury, functions of the lower urinary tract may be disrupted. A wearable device with surface electrodes which can effectively control the bladder functions would be highly beneficial to the patients. A trans-rectal pudendal nerve stimulator may provide such a solution. However, the major limiting factor in such a stimulator is the high level of current it requires to recruit the nerve fibers. Also, the variability of the trajectory of the nerve in different individuals should be considered. Using computational models and an approximate trajectory of the nerve derived from an MRI study, it is demonstrated in this paper that it may be possible to considerably reduce the required current levels for trans-rectal stimulation of the pudendal nerve compared to the values previously reported in the literature. This was corroborated by considering an ensemble of possible and probable variations of the trajectory. The outcome of this study suggests that trans-rectal stimulation of the pudendal nerve is a plausible long term solution for treating lower urinary tract dysfunctions after spinal cord injury

A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. We investigated the efficacy and safety of CHF6001 using the allergen challenge model in a double blind, placebo controlled, 3-way cross-over study. Thirty six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.2). Compared with placebo, CHF 6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma

Design of sEMG assembly to detect external anal sphincter activity: a proof of concept

Objective: Conditional trans-rectal stimulation of the pudendal nerve could provide a viable solution to treat hyperreflexive bladder in spinal cord injury. A set threshold of the amplitude estimate of the external anal sphincter surface electromyography (sEMG) may be used as the trigger signal. The efficacy of such a device should be tested in a large scale clinical trial. As such a probe should remain in situ for several hours while patients attend to their daily routine, the recording electrodes should be designed to be large enough to maintain good contact while observing design constraints. The objective of this study was to arrive at a design for intra-anal sEMG recording electrodes for the subsequent clinical trials while deriving the possible recording and processing parameters. &#13; Approach: Having in mind existing solutions and based on theoretical and anatomical considerations, a set of four multi-electrode probes were designed and developed. These were tested in a healthy subject and the measured sEMG traces were recorded and appropriately processed.&#13; Main results: It was shown that while comparatively large electrodes record sEMG traces that are not sufficiently correlated with the external anal sphincter contractions, smaller electrodes may not maintain a stable electrode tissue contact. It was shown that 3 mm wide and 1 cm long electrodes with 5 mm inter-electrode spacing, in agreement with Nyquist sampling, placed 1 cm from the orifice may intra-anally record a sEMG trace sufficiently correlated with external anal sphincter activity.&#13; Significance: The outcome of this study can be used in any biofeedback, treatment or diagnostic application where the activity of the external anal sphincter sEMG should be detected for an extended period of time

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.</p> <p>Methods</p> <p>Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV₁, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV₁area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV₁and analysis of variance for AMP challenge.</p> <p>Results</p> <p>Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV₁was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.</p> <p>Conclusions</p> <p>The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01343745">NCT01343745</a></p

The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions.

Abstract AIMS: The aim of the present study was to investigate whether selective antagonism of the cysteine-X-cysteine chemokine receptor-2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens. METHODS: In a double-blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte-colony stimulating factor (G-CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli. RESULTS: AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of -1.67 (0.67) ×10(9) l(-1) vs. 0.19 (0.78) ×10(9) l(-1) for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10-min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G-CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo- and AZD5069-treated subjects. Superoxide anion production in E. coli-stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated. CONCLUSIONS: CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role