Targeting granulocyte apoptosis: mechanisms,models, and therapies

Summary: The inflammatory process is a complex series of tightly controlled cellular and biochemical events initiated by the immune system, which has evolved to eliminate or contain infectious agents and to repair damaged tissue. Apoptosis is essential for the clearance of potentially injurious inflammatory cells, such as neutrophils, eosinophils, and basophils, and the subsequent efficient resolution of inflammation. In this review, we aim to cover key features of the granulocyte life-cycle ranging from their differentiation within the bone marrow to their maturation and ultimate clearance, with a focus on granulocyte apoptosis and macrophage efferocytosis. We further aim to discuss current and emerging models of inflammation and suggest novel ways of terminating or resolving deleterious inflammatory responses with a specific view to the translation of these strategies into fully realized, pro-resolution therapies.     

The social construction of chronicity – a key to understanding chronic care transformations

Purpose The purpose of this paper is to argue the importance of contemporary analysis of the modern social construction of chronicity – encapsulating the world views of the chronically ill, and the medical and health system constructions of chronic disease, through the nature of care for chronic conditions. It is argued that chronic diseases are themselves, socially constructed, despite widely accepted disease classification systems. Thus, there is a need to examine how different ideas have permeated our clinical and health system developments and their social context and vice versa. Methods We examine historical ideas, theory and evidence about the tensions in social construction of chronic illness by those afflicted and the responses of society, the medical and health professions and increasingly the public and private institutions that shape health care. This is with the background of major differences in the two cultures that create knowledge: those based upon argument and intellectual logic – hermeneutic, and those based upon ‘objectivist’ empirical science, often called heuristic. Evidence‐based medicine (EBM) is the flagship of disease management, increasingly narrative‐based medicine and other similar genres are becoming the pragmatic face of social constructions, yet sit in juxtaposition without synthesis. A third culture has emerged of scientific intellectuals who straddle these cultures and in health care their public face is ‘mixed methods’. Findings Recent cases of modern ideas about improving chronic care were reviewed. We found that despite developments of social theory, the world view of the chronically ill exerts small influence in health system redesign, apparently dominated by chronic disease models. Confusion remains within health system reforms as to the social construction of chronicity – chronic disease, chronic condition or chronic illness and chronic care transformations. The role of Primary Care remains ambiguous straddling disease and illness. Radical redesign of health systems is taking place without an understanding and discourse about the nature of their construction. Ad hoc eclectism with unquestioning adoption of the dominant EBM paradigm is driving a new health culture based on disease‐based performance incentives, which is intrusive beyond the medical model and pays little attention to narratives of illness and even less to the whole social reconstruction of illness and wellness. Conclusions Health care systems cannot afford to avoid, and should actively embrace the critiques of social theory and analyses in the transformations of health systems to improve chronic care. Creative tensions between empirical and intellectual critique, and a synthetic middle ground are likely to lead to more realistic and innovative approaches spanning the nature of chronicity and the transformation of Primary Care.     

Advanced life support performance with manual and mechanical chest compressions in a randomized,multicentre manikin study

Aim of the studyClinical mechanical chest compression studies report diverging outcomes. Confounding effects of variability in hands-off fraction (HOF) and timing of necessary tasks during advanced life support (ALS) may contribute to this divergence. Study site variability in these factors coupled to randomization of cardiopulmonary resuscitation (CPR) method was studied during simulated cardiac arrest prior to a multicentre clinical trial.MethodAmbulance personnel from four sites were tested in randomized, simulated cardiac arrest scenarios with manual CPR or load-distributing band CPR (LDB-CPR) on manikins. Primary emphasis was on HOF and time spent before necessary predefined ALS task (ALS milestones). Results are presented as mean differences (confidence interval).ResultsAt the site with lowest HOF during manual CPR, HOF deteriorated with LDB-CPR by 0.06 (0.005, 0.118, p = 0.04), while it improved at the two sites with highest HOF during manual CPR by 0.07 (0.019, 0.112, p = 0.007) and 0.08 (0.004, 0.165, p = 0.042). Initial defibrillation was 29 (3, 55, p = 0.032) s delayed for LDB-CPR vs. manual CPR. Other ALS milestones trended toward earlier completion with LDB-CPR; only significant for intravenous access, mean difference 70 (24, 115, p = 0.003) s.ConclusionIn this manikin study, HOF for manual vs. mechanical chest compressions varied between sites. Study protocol implementation should be simulation tested before launching multicentre trials, to optimize performance and improve reliability and scientific interpretation.     

Paediatric stroke: The need for interdisciplinary models of care

Abstract:   Stroke is an important cause of mortality and long-term morbidity in children. The aetiology of stroke in childhood differs from that of adults, with vasculopathies and congenital heart disease being the most commonly identified risk factors. Recognition and diagnosis are often delayed, limiting access to acute medical interventions such as thrombolysis. Optimal management of stroke in children is still not known and existing guidelines are at the level of expert consensus. Interdisciplinary childhood stroke programmes are required to meet the needs of this population and to contribute to the development of evidence-based therapies.     

High-throughput multistrain polymerase chain reaction quantification of Chlamydia trachomatis from clinical and preclinical urogenital specimens

Chlamydia trachomatis (CT) is the most prevalent sexually transmitted bacterial pathogen worldwide and causes severe reproductive tract infections. Currently, nucleic acid amplification tests (NAATs) are the gold standard for clinical diagnosis, but most NAATs are labor intensive and limited to specific CT serovars. We developed and validated a quantitative polymerase chain reaction (qPCR) assay that reproducibly detected CT serovars D, E, F, Ia, and Chlamydia muridarum over a linear range of 2 log₁₀ to 10 log₁₀ genomes with low coefficients of variation from both experimental and human urine samples. CT DNA loads from human vaginal, endocervical, and male urethral swabs correlated well with the BD ProbeTec ET assay (Becton Dickinson Diagnostic Systems, Franklin Lakes, NJ) run in parallel. In a preclinical microbicide evaluation, C. muridarum DNA loads in mouse swabs and tissues correlated well with an immunofluorescence assay. The optimized qPCR system provided enhanced sensitivity and facilitated the quantitative evaluation of clinical and experimental preclinical samples for anti-CT therapeutic and microbicide evaluation.     

Rapid synthesis of a 13C6‐benzothiazolium salt from 13C6‐aniline

¹³C₆‐labeled aniline was used as a starting material for the facile synthesis of ¹³C₆‐benzothiazolium salt ( 1 ). Copyright © 2011 John Wiley & Sons, Ltd.     

The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas

Background and objectives Transsphenoidal surgery is indicated for patients with nonfunctioning pituitary adenomas (NFPAs) causing compressive symptoms. Previous studies attempting to define the rate of recurrence/regrowth of surgically treated but radiation‐naïve NFPAs were somewhat limited by selection bias and/or small numbers and/or lack of consistency of findings between studies. A better understanding of the natural history of this condition could allow stratification of recurrence risk and inform future management. We aimed to define the natural history of a large, mainly unselected cohort with surgically treated, radiotherapy (RT)‐naïve NFPAs and to try to identify predictors of recurrence/regrowth. Design Case‐note analysis of all patients who underwent surgery for NFPA in our hospital between 1980 and 2006 was undertaken. Median follow‐up was 5·7 (range 1–25) years. Patients A total of 212 patients were identified of which 159 were suitable for analysis. 93% did not receive post‐operative RT. Measurement Post‐operative recurrent/regrowth was defined by any increase in tumour remnant size on serial post‐operative pituitary imaging. Results Recurrence/regrowth was documented in 53 patients (33·5%). Multivariate analysis revealed size of the post‐operative tumour remnant and length of follow‐up to be the two major determinants of recurrence/regrowth. The presence of a tumour with an extrasellar remnant was associated with the highest risk of recurrence (odds ratio 3·73 [CI: 1·97–7·09]), while no recurrence was seen in those with no residual tumour post‐operatively and regrowth risk was intermediate for those with remaining intrasellar remnant. Conclusion These results indicate that patients with post‐operative tumour with an extrasellar remnant should be considered routinely for adjuvant RT to reduce the risk of tumour regrowth while those with no residual tumour can be safely observed. Individualized decisions should be made for patients with an intrasellar remnant.