The Meaning of Life: A Merleau-Pontian Investigation of How Living Bodies Make Sense

Thesis advisor: Jeffrey BloechlThis dissertation takes up Maurice Merleau-Ponty's unfinished project of developing an ontology of nature whose concepts are drawn from the phenomenon of life, rather than from human techne. I argue that the question of life has been hopelessly obscured by the collapse, in the Modern era, of the distinction between nature and artifice. We cannot hope to understand the difference between life and non-life until we understand the difference between the living body and the machine. Merleau-Ponty's constant aim was to show that the living body is not a blind mechanism, and that the body has its own endogenous sense which is not projected onto it by a disembodied consciousness. Central to these efforts were the phenomena of learning and development, and the concept of form or Gestalt. Development is what distinguishes the living body, which is an open-ended process of becoming, from the machine, whose possibilities are determined in advance by its creator. In order to conceptualize the phenomenon of development, Merleau-Ponty appropriated from psychology the concept of form (Gestalt): a dynamic, self-organizing whole that cannot be decomposed into independent parts. Where the conception of nature as mechanism implies that everything is determined in advance, Merleau-Ponty's conception of nature as Gestalt allows for the genesis of genuinely new phenomena through nature's own self- organizing movement. We would thus be able to understand the genesis of sense in nature as a process of morphogenesis--the genesis of form. However, Merleau-Ponty struggled to clarify the ontological status of form. He lacked the conceptual resources to explain form in its own terms, rather than by contrast with the decomposable wholes of human artifice. This dissertation attempts to locate these conceptual resources in the science of complexity that has emerged since Merleau- Ponty's death, and whose descriptions of complex systems are uncannily anticipated in Merleau-Ponty's writings. I take from this new science the conception of form as asymmetry or difference, and of morphogenesis as symmetry-breaking or self-differentiation. In order to investigate how meaning emerges out of form, I turn to recent work in biology and psychology that applies the concept of symmetry-breaking to the phenomena of anatomical growth and motor development. By studying the development of the living body and its behavior, I show how nature articulates itself into perceiver and perceived. In the movement of the living body, form folds back upon itself, giving rise to a new kind of meaning: a pre-reflective, motor significance that is neither mechanism nor mental representation. In Chapter One, I distinguish the living body from a machine or artifact by distinguishing between manufacturing and growth. This distinction, which seemed obvious to the Ancients, has been obscured by Modern science's pivotal decision to treat nature as if it were a product of human artifice. This decision has committed us to an atomistic ontology, which takes nature to be a synthetic whole composed of mutually indifferent parts. However, this ontology faces a basic problem, which I call the problem of form: how to explain the synthesis of indifferent atoms into the complex, harmonious wholes we observe in nature, without appealing to an intelligent designer. Nowhere is this problem more acute than in the phenomenon of anatomical development or embryogenesis. I argue that biology has been unable to explain this phenomenon in mechanical or atomistic terms: the Neo-Darwinist view of the living body as a synthetic whole determined in advance by a genetic blueprint or program has succeeded not by explaining development, but rather by ignoring it. In Chapter Two, I argue that the problem of form--and of living form in particular--can only be resolved by abandoning our atomistic ontology, and with it our synthetic understanding of form as a shape imposed on an indifferent material. Recent developments in the science of complexity have yielded a new definition of form as asymmetry or difference. On this view, the genesis of form in nature is not the synthesis of wholes out of pre-existing parts, but the self-differentiation of wholes into parts through symmetry-breaking. In order to understand how natural wholes become less symmetrical over time, I introduce three further concepts from the science of complexity: nonlinearity, stability, and instability. With these concepts in hand, I return to the problem of embryogenesis, in order to show how complex living forms can develop reliably and robustly without being determined in advance by a design or program. In Chapter Three, I turn from anatomical development to the development of behavior, in order to see how the genesis of form becomes a genesis of sense. I begin by criticizing three mechanistic theories of behavior--Behaviorism, Cognitivism, and Connectionism--which suffer from the same problem of form that plagues mechanistic theories of anatomical development. Behavior grows like an organ: by symmetry-breaking, not by synthesis. Learning is not a matter of association, but of differentiation: the perception of increasingly subtle asymmetries in the body's environment through increasingly asymmetrical movements. It is the world that teaches the organism how to move--but a world that is only revealed to the organism by its own movements. Thus the living body and its world grow together dialectically, each driving the other to become more determinate through its own increasing determinacy.Thesis (PhD) — Boston College, 2012.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Philosophy

Earth Mover’s Distance (EMD): A True Metric for Comparing Biomarker Expression Levels in Cell Populations

Changes in the frequencies of cell subsets that (co)express characteristic biomarkers, or levels of the biomarkers on the subsets, are widely used as indices of drug response, disease prognosis, stem cell reconstitution, etc. However, although the currently available computational “gating” tools accurately reveal subset frequencies and marker expression levels, they fail to enable statistically reliable judgements as to whether these frequencies and expression levels differ significantly between/among subject groups. Here we introduce flow cytometry data analysis pipeline which includes the Earth Mover’s Distance (EMD) metric as solution to this problem. Well known as an informative quantitative measure of differences between distributions, we present three exemplary studies showing that EMD 1) reveals clinically-relevant shifts in two markers on blood basophils responding to an offending allergen; 2) shows that ablative tumor radiation induces significant changes in the murine colon cancer tumor microenvironment; and, 3) ranks immunological differences in mouse peritoneal cavity cells harvested from three genetically distinct mouse strains

Early use of remote dielectric sensing after hospitalization to reduce heart failure readmissions

Readmission after hospitalization for acute decompensated heart failure (HF) remains a major public health problem. Use of remote dielectric sensing (ReDS) to measure lung water volume allows for an objective assessment of volume status and may guide medical optimization for HF. We hypothesized that the use of ReDS would lower 30 day readmission in patients referred to rapid follow-up (RFU) clinic after HF discharge. We conducted a retrospective analysis of the use of ReDS for patients scheduled for RFU within 10 days post-discharge for HF at Mount Sinai Hospital between 1 July 2017 and 31 July 2018. Diuretics were adjusted using a pre-specified algorithm. The association between use of ReDS and 30 day readmission was evaluated. A total of 220 patients were included. Mean age was 62.9 ± 14.7 years, and 36.4% were female. ReDS was performed in 80 (36.4%) and led to medication adjustment in 52 (65%). Use of ReDS was associated with a lower rate of 30 day cardiovascular readmission [2.6% vs. 11.8%, hazard ratio (HR): 0.21; 95% confidence interval (CI): 0.05-0.89; P = 0.04] and a trend towards lower all-cause readmission (6.5% vs. 14.1%, HR: 0.43; 95% CI: 0.16-1.15; P = 0.09) as compared with patients without a ReDS assessment. ReDS-guided HF therapy during RFU after HF hospitalization may be associated with lower risk of 30 day readmission

Are interactions the primary triggers of star formation in dwarf galaxies?

We investigate the assumption that the trigger of star formation in dwarf galaxies are interactions with other galaxies, in the context of a search for a "primary" trigger of a first generation of stars. This is cosmologically relevant because the galaxy formation process consists not only of the accumulation of gas in a gravitational potential well, but also of the triggering of star formation in this gas mass and also because some high-z potentially primeval galaxy blocks look like nearby star-forming dwarf galaxies. We review theoretical ideas proposed to account for the tidal interaction triggering mechanism and present a series of observational tests of this assumption using published data. We show also results of a search in the vicinity of a composite sample of 96 dwarf late-type galaxies for interaction candidates showing star formation. The small number of possible perturbing galaxies indentified in the neighborhood of our sample galaxies, along with similar findings from other studies, supports the view that tidal interactions may not be relevant as primary triggers of star formation. We conclude that interactions between galaxies may explain some forms of star formation triggering, perhaps in central regions of large galaxies, but they do not seem to be significant for dwarf galaxies and, by inference, for first-time galaxies forming at high redshifts. Intuitive reasoning, based on an analogy with stellar dynamics, shows that conditions for primary star formation triggering may occur in gas masses oscillating in a dark matter potential. We propose this mechanism as a plausible primary trigger scenario, worth investigating theoretically.Comment: Accepted for publication in MNRA

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis

Background: Respiratory tract infection with Pseudomonas aeruginosa occurs inmost people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an update of a Cochrane review first published in 2003, and previously updated in 2006 and 2009. Objectives: To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms). Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 08 September 2014. Selection criteria: We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. Data collection and analysis: Both authors independently selected trials, assessed risk of bias and extracted data. Main results: The search identified 49 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used. Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months. One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% confidence interval 0.02 to 0.79). One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non- inferiority or equivalence. A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups. A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). Authors’ conclusions: We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials of two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Granular cell tumor of the bronchus

Persistent atelectasis and recurrent pneumonia in the same location should raise suspicion of congenital anomalies or obstructing lesions of the bronchus leading to the affected area. We present an 8-year-old black female with a history of recurrent fever, cough, atelectasis of the right middle and lower lobes, and weight loss for several months. Flexible bronchoscopy revealed a polypoid mass obstructing the bronchus intermedius. Biopsy of the neoplasm demonstrated a granular cell tumor (GCT). The patient had a lobectomy of the right lower and middle lobes. She had no recurrence of the tumor after several years of follow-up. Pediatr Pulmonol. 2000; 30:425–428. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35317/1/9_ftp.pd