Concise Review: Mesenchymal Stem Cells for Acute Lung Injury: Role of Paracrine Soluble Factor

Morbidity and mortality have declined only modestly in patients with clinical acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), despite extensive research into the pathophysiology. Current treatment remains primarily supportive with lung-protective ventilation and a fluid conservative strategy. Pharmacologic therapies that reduce the severity of lung injury in preclinical models have not yet been translated to effective clinical treatment options. Consequently, further research in translational therapies is needed. Cell-based therapy with mesenchymal stem cells (MSCs) is one attractive new therapeutic approach. MSCs have the capacity to secrete multiple paracrine factors that can regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. This review will focus on recent studies, which support the potential therapeutic use of MSCs in ALI/ARDS, with an emphasis on the role of paracrine soluble factors.

A Unified Scheduler for Recursive and Task Dataflow Parallelism

Task dataflow languages simplify the specification of parallel programs by dynamically detecting and enforcing dependencies between tasks. These languages are, however, often restricted to a single level of parallelism. This language design is reflected in the runtime system, where a master thread explicitly generates a task graph and worker threads execute ready tasks and wake-up their dependents. Such an approach is incompatible with state-of-the-art schedulers such as the Cilk scheduler, that minimize the creation of idle tasks (work-first principle) and place all task creation and scheduling off the critical path. This paper proposes an extension to the Cilk scheduler in order to reconcile task dependencies with the work-first principle. We discuss the impact of task dependencies on the properties of the Cilk scheduler. Furthermore, we propose a low-overhead ticket-based technique for dependency tracking and enforcement at the object level. Our scheduler also supports renaming of objects in order to increase task-level parallelism. Renaming is implemented using versioned objects, a new type of hyper object. Experimental evaluation shows that the unified scheduler is as efficient as the Cilk scheduler when tasks have no dependencies. Moreover, the unified scheduler is more efficient than SMPSS, a particular implementation of a task dataflow language.

Surveillance for ocular hypertension: An evidence synthesis and economic evaluation

OBJECTIVES: To determine effective and efficient monitoring criteria for ocular hypertension [raised intraocular pressure (IOP)] through (i) identification and validation of glaucoma risk prediction models; and (ii) development of models to determine optimal surveillance pathways.

DESIGN: A discrete event simulation economic modelling evaluation. Data from systematic reviews of risk prediction models and agreement between tonometers, secondary analyses of existing datasets (to validate identified risk models and determine optimal monitoring criteria) and public preferences were used to structure and populate the economic model.

SETTING: Primary and secondary care.

PARTICIPANTS: Adults with ocular hypertension (IOP > 21 mmHg) and the public (surveillance preferences).

INTERVENTIONS: We compared five pathways: two based on National Institute for Health and Clinical Excellence (NICE) guidelines with monitoring interval and treatment depending on initial risk stratification, 'NICE intensive' (4-monthly to annual monitoring) and 'NICE conservative' (6-monthly to biennial monitoring); two pathways, differing in location (hospital and community), with monitoring biennially and treatment initiated for a ≥ 6% 5-year glaucoma risk; and a 'treat all' pathway involving treatment with a prostaglandin analogue if IOP > 21 mmHg and IOP measured annually in the community.

MAIN OUTCOME MEASURES: Glaucoma cases detected; tonometer agreement; public preferences; costs; willingness to pay and quality-adjusted life-years (QALYs).

RESULTS: The best available glaucoma risk prediction model estimated the 5-year risk based on age and ocular predictors (IOP, central corneal thickness, optic nerve damage and index of visual field status). Taking the average of two IOP readings, by tonometry, true change was detected at two years. Sizeable measurement variability was noted between tonometers. There was a general public preference for monitoring; good communication and understanding of the process predicted service value. 'Treat all' was the least costly and 'NICE intensive' the most costly pathway. Biennial monitoring reduced the number of cases of glaucoma conversion compared with a 'treat all' pathway and provided more QALYs, but the incremental cost-effectiveness ratio (ICER) was considerably more than £30,000. The 'NICE intensive' pathway also avoided glaucoma conversion, but NICE-based pathways were either dominated (more costly and less effective) by biennial hospital monitoring or had a ICERs > £30,000. Results were not sensitive to the risk threshold for initiating surveillance but were sensitive to the risk threshold for initiating treatment, NHS costs and treatment adherence.

LIMITATIONS: Optimal monitoring intervals were based on IOP data. There were insufficient data to determine the optimal frequency of measurement of the visual field or optic nerve head for identification of glaucoma. The economic modelling took a 20-year time horizon which may be insufficient to capture long-term benefits. Sensitivity analyses may not fully capture the uncertainty surrounding parameter estimates.

CONCLUSIONS: For confirmed ocular hypertension, findings suggest that there is no clear benefit from intensive monitoring. Consideration of the patient experience is important. A cohort study is recommended to provide data to refine the glaucoma risk prediction model, determine the optimum type and frequency of serial glaucoma tests and estimate costs and patient preferences for monitoring and treatment.

FUNDING: The National Institute for Health Research Health Technology Assessment Programme.

"Angels and Demons in Cromwellian and Restoration Ireland: Heresy and the Supernatural"

This essay explores accounts of supernatural activity in Cromwellian and Restoration Ireland. Religious life in Cromwellian Ireland was driven by expectations of the unusual—including audible voices from heaven, material encounters with angels, and spiritual encounters with demons. Some conservative Protestants linked this activity to the development and dissemination of heretical belief, while some who had such encounters were confident that it was compatible with the Cromwellian religious mainstream. Crawford Gribben explores the flexibility in the discourse of the marvelous in Ireland and the ways in which the administration contributed to it, and the alignment of the supernatural with various confessional convictions and postures, as well as theological radicalism. After the Restoration, accounts of supernatural encounters were remembered as ghost stories, not as matters for theological debate, a cultural transition linked to the development of a historiography that has continued to invest the Irish Cromwellian past with Gothic tropes.

Cold War Politics in Britain and the Contested Legacy of the Spanish Civil War

This article offers a sustained examination of how the vicissitudes of the Cold War shaped changing interpretations of the Spanish Civil War in Britain. Considering the perspectives of participants and historians, it focuses on the diverse strands of the Left that frequently drew on the civil war to attack each other and to make wider arguments about the global Cold War. First, with the aim of criticizing Communist take-overs in Eastern Europe in the late 1940s, the article analyzes retrospective assaults on Communist party tactics and Soviet foreign policy in Spain. Second, in order to argue that the Soviet Union took a counter-revolutionary line after 1956, it investigates the re-emergence of debates over the Spanish revolution. Third, to express disapproval of the United States, it examines the increasing use of the civil war as an analogy in Cold War international affairs from the 1960s. Fourth, in support of non-Soviet Left-of-Centre collaboration, most notably Eurocommunism in the 1970s and opposition to Margaret Thatcher’s Conservative government in the 1980s, it considers the renewed emphasis on the popular front. The trajectories of these debates reveal that, over time, the weight of the Left’s criticism moved from the Soviet Union towards the United States.

Fabricating Economic Development

This paper is concerned with the institutions of Irish economics; it is structured around two arguments each of which links to the thesis presented in Garvin’s Preventing the future (2004). Overall it will be demonstrated that Irish economics was shaped by intellectual trends experienced within economic thought globally as well as the social considerations that were peculiar to Ireland. The evidence presented indicates that firstly while Economic Development mattered to the Irish economy it did not matter for the reasons that most writers have suggested it did. It is argued for instance that much of the literature, regardless of academic discipline, presents the publication of Economic Development in 1958 as analogous to a “big bang” event in the creation of modern Ireland. However, such a “big bang” perspective misrepresents the sophistication of economic debates prior to Whitaker’s report as well as distorting the interpretation of subsequent developments. The paper secondly, by drawing on the contents of contemporary academic journals, reappraises Irish economic thinking before and after the publication of Economic Development. It is argued that an economically “liberal” approach to Keynesianism, such as that favoured by TK Whitaker and George O’Brien, lost out in the 1960s to a more interventionist approach: only later did a more liberal approach to macroeconomic policy triumph. The rival approaches to academic economics were in turn linked to wider debates on the influence of religious authorities on Irish higher education. Academic economists were particularly concerned with preserving their intellectual independence and how a shift to planning would keep decisions on resource allocation out of the reach of conservative political and religious leaders.

Eve and evolution: Christian responses to the first woman question, 1860-1900

Historians of encounters between evolutionary science and Christianity have long been aware of the significance placed upon debates about the applicability of evolution to Adam. It has not been widely noticed, however, that in more conservative circles the creation of Eve was frequently thought to be a more difficult problem to solve. This essay examines how, in distinctive ways, the creation of Eve became a point of contention among three communities of conservative Christian thinkers grappling with the implications of evolutionary theory in the period 1860-1900.

Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency:structure-function relationships and studies in a compound heterozygous proband

Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency. Exon sequence determination of the LCAT gene of the proband revealed two novel heterozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino acid substitutions (Thr13Met and Pro307Ser, respectively). To assess the distinct functional impact of the separate mutant alleles, studies were conducted in the proband's 3-generation pedigree. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband's mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. The proband's father and two daughters were heterozygous for the Thr13Met mutation and also displayed low HDL, reduced LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely impaired in the compound heterozygous proband and was reduced by 50% in individuals heterozygous for either mutation, compared to wild type family members. It is also shown that the two mutations impair both catalytic activity and expression of the circulating protein.

Development of novel oral formulations prepared via hot melt extrusion for targeted delivery of photosensitizer to the colon

Colon-residing bacteria, such as vancomycin-resistant Enterococcus faecalis and Bacteroides fragilis, can cause a range of serious clinical infections. Photodynamic antimicrobial chemotherapy (PACT) may be a novel treatment option for these multidrug resistant organisms. The aim of this study was to formulate a Eudragit®-based drug delivery system, via hot melt extrusion (HME), for targeting colonic release of photosensitizer. The susceptibility of E. faecalis and B. fragilis to PACT mediated by methylene blue (MB), meso-tetra(N-methyl-4-pyridyl)porphine tetra-tosylate (TMP), or 5-aminolevulinic acid hexyl-ester (h-ALA) was determined, with tetrachlorodecaoxide (TCDO), an oxygen-releasing compound, added in some studies. Results show that, for MB, an average of 30% of the total drug load was released over a 6-h period. For TMP and h-ALA, these values were 50% and 16% respectively. No drug was released in the acidic media. Levels of E. faecalis and B. fragilis were reduced by up to 4.67 and 7.73 logs, respectively, on PACT exposure under anaerobic conditions, with increased kill associated with TCDO. With these formulations, photosensitizer release could potentially be targeted to the colon, and colon-residing pathogens killed by PACT. TCDO could be used in vivo to generate oxygen, which could significantly impact on the success of PACT in the clinic.

Hip protectors to prevent hip fractures - a waste of time and money?

Abstract:
Background: An estimated 30-60% of older
adults fall every year and about 1% of falls result in a hip fracture. Hip fracture is a serious and growing problem, with a 3-10 fold rise in worldwide incidence predicted by 2050 (Gullberg, et al 1997). Hip protectors are underwear with built in protection for the greater trochanter. They are designed to prevent hip fractures by dispersing or absorbing the force of a fall. Trials
published to 2001 were broadly supportive of
the effectiveness of hip protectors, and this
was reflected in a Cochrane review in 2000.
However, earlier trials were methodologically
flawed and subsequent trials have not demonstrated effectiveness. The most recent Cochrane review describes only a marginal benefit (Parker et al, 2005).
Review and Discussion: This presentation
evaluates the current evidence for the use
of hip protectors and discusses the use of
that evidence by manufacturers, suppliers,
professional groups and guideline developers.
Interestingly, despite the limitations of the
evidence base, most advice has been broadly
supportive. Reasons for this are proposed
and discussed in the context of a critique of
evidence-based healthcare. protectors. However, the available evidence can be used in different ways and for different purposes by those with an interest in promoting
the use of hip protectors. A conservative
approach is warranted, where, if we cannot
demonstrate that hip protectors work, we
presume that they do not. This presentation will be of use to practitioners wanting to evaluate the evidence base for hip protectors (and other recommended interventions) on behalf of clients. It will also be of interest to policy makers who must assess the claims made for health care technologies as part of the decisionmaking process.
Recommended reading:
Gullberg B, Johnell O, Kanis JA (1997) Worldwide
projections for hip fracture. Osteoporos
Int. 7(5):407-13 .
Parker MJ, Gillespie WJ, Gillespie LD (2005) Hip
protectors for preventing hip fractures in older
people. The Cochrane Database of Systematic
Reviews Issue 3. Art. No.: CD001255.pub3. DOI:
10.1002/14651858.CD001255.pub3.

Religion and the risk of suicide: longitudinal study of over 1 million people

Background: Durkheim’s seminal historical study demonstrated that religious affiliation reduces suicide risk, but it is unclear whether this protective effect persists in modern, more secular societies.

Aims: To examine suicide risk according to Christian religious affiliation and by inference to examine underlying mechanisms for suicide risk. If church attendance is important, risk should be lowest for Roman Catholics and highest for those with no religion; if religiosity is important, then ‘conservative’ Christians should fare best.

Method: A 9-year study followed 1 106 104 people aged 16–74 years at the 2001 UK census, using Cox proportional hazards models adjusted for census-based cohort attributes.

Results: In fully adjusted models analysing 1119 cases of suicide, Roman Catholics, Protestants and those professing no religion recorded similar risks. The risk associated with conservative Christians was lower than that for Catholics (HR = 0.71, 95% CI 0.52–0.97).

Conclusions: The relationship between religious affiliation and suicide established by Durkheim may not pertain in societies where suicide rates are highest at younger ages. Risks are similar for those with and without a religious affiliation, and Catholics (who traditionally are characterised by higher levels of church attendance) do not demonstrate lower risk of suicide. However, religious affiliation is a poor measure of religiosity, except for a small group of conservative Christians, although their lower risk of suicide may be attributable to factors such as lower risk behaviour and alcohol consumption.

Considering Just-World Thinking in Counter-Terrorism Cases: Miscarriages of Justice in Northern Ireland

Recent literature has drawn a parallel between the discriminatory application of counterterrorism legislation to the Irish population in the United Kingdom during the Northern Ireland conflict and the targeting of Muslims after September 2001. Less attention has been paid to lessons that can be drawn from judicial decision making in terrorism-related cases stemming from the Northern Ireland conflict. This Article examines Northern Ireland Court of Appeal (“NICA”) jurisprudence on miscarriages of justice in cases regarding counterterrorism offenses. In particular, the Article focuses on cases referred after the 1998 peace agreements in Northern Ireland from the Criminal Cases Review Commission (“CCRC”), a relatively new entity that investigates potential wrongful convictions in England, Wales, and Northern Ireland. Although the NICA’s human rights jurisprudence has developed significantly in recent years, the study of CCRC-referred cases finds that judges have retained confidence in the integrity of the conflict-era counterterrorism system even while acknowledging abuses and procedural irregularities that occurred. This study partially contradicts contentions that judicial deference to the executive recedes in a post-conflict or post-emergency period. Despite a high rate of quashed convictions, the NICA’s decisions suggest that it seeks to limit a large number of referrals and demonstrate a judicial predisposition to defend the justness of the past system’s laws and procedure. This perspective is consistent with what social psychologists have studied as “just-world thinking,” in which objective observers, although motivated by a concern with justice, believe—as a result of cognitive bias—that individuals “got what they deserved.” The Article considers other potential interpretations of the jurisprudence and contends that conservative decision making is particularly dangerous in the politicized realm of counterterrorism and in light of the criminalization of members of suspect communities.