Castleman disease and lymphocytic interstitial pneumonia: a complex diagnostic and management challenge

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Endothelin-1 and the use of induced sputum to investigate its role in airway diseases

Endothelin (ET)-1 is a 21-amino acid peptide which has been the subject of intense interest since its discovery in 1988. It has a number of properties which may be important in physiology and pathophysiology, including potential relevance to airway diseases. A putative role for ET-1 in asthma has been proposed, and we sought to examine this further, as well as to extend our investigations to other respiratory diseases, including chronic obstructive pulmonary disease and cystic fibrosis. The technique of sputum induction has been developed recently as a non-invasive method of obtaining airway secretions for analysis, and we have applied this to the investigation of the role of ET-1 in diseases involving the airway. We have demonstrated for the first time that ET-1 is a highly potent bronchoconstrictor with a prolonged duration of action when administered by aerosol in asthma, and that asthmatics exhibit bronchial hyperreactivity to ET-1 compared with non-asthmatic subjects, but we found no evidence of an acute inflammatory airway response at 30 minutes or 4 hours following ET-l-induced bronchoconstriction in asthma, assessed by analysis of cell counts and soluble mediators in induced sputum. The bronchoconstrictor activity of ET-1 was not potentiated by an infusion of angiotensin II in stable asthmatics, despite animal evidence of potentiation, although the possibility of such interaction remains in acute severe asthma, where plasma angiotensin II levels are elevated. We did not find increased levels of ET-1 in induced sputum in mild asthmatics compared with non-asthmatic subjects, nor was there a fall in sputum ET-1 comparing samples obtained during acute severe asthma with those obtained in convalescence, although sputum and saliva levels of ET-1 are greater than plasma ET-1, suggesting local production within the respiratory tract. Examination of sputum ET-1 following allergen challenge in asthma showed a trend towards an increase in sputum ET-1 after allergen challenge, with a relationship between the increase in sputum ET-1 and the extent of sputum eosinophilia, suggesting a relationship between asthmatic airway inflammation and ET- 1 release. Sputum ET-1 is increased in smokers without lung disease, and in subjects with chronic obstructive pulmonary disease (COPD), with a trend towards a fall in sputum ET-1 comparing acute exacerbation with convalescence. Finally, we have demonstrated a marked increase in sputum ET-1 in patients with cystic fibrosis compared with healthy subjects. We conclude from this series of studies that there is continuing evidence for a role for ET-1 in a number of diseases affecting the airway, and speculate that drugs which oppose the action of ET-1 may have a role in the treatment of these conditions

Seasonality in Human Zoonotic Enteric Diseases: A Systematic Review

BACKGROUND: Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini  0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18). CONCLUSIONS/SIGNIFICANCE: Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries

Three (Potential) Pillars of Transnational Economic Justice: The Bretton Woods Institutions as Guarantors of Global Equal Treatment and Market Completion

This essay aims to bring two important lines of inquiry and criticism together. It first lays out an institutionally enriched account of what a just world economic order will look like. That account prescribes, via the requisites to that mechanism which most directly instantiate the account, three realms of equal treatment and market completion - the global products, services, and labor markets; the global investment/financial markets; and the global preparticipation opportunity allocation. The essay then suggests how, with minimal if any departure from familiar canons of traditional international legal mandate interpretation, each of the Bretton Woods institutions - particularly the GATT/WTO and the IMF - can be viewed at least in part as charged with the task of fostering equal treatment and ultimate market completion within one of those three realms. The piece then argues that one of the institutions in particular - the World Bank - has, for reasons of at best negligent and at worst willful injustice on the part of influential state actors in the world community, fallen farthest short in pursuit of what should be viewed as its proper mandate. The article accordingly concludes that a fuller empowerment of the Bank to effect its ideal mission will press the Bretton Woods system more nearly into ethical balance, and with it the world into justice; and that full empowerment of the GATT/WTO and IMF should be partly conditioned upon the fuller empowerment of the Bank

Updated guidance on the management of COVID-19:from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020)

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. METHODS: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. RESULTS: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. CONCLUSIONS: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.status: Published onlin

Absence of N addition facilitates B cell development, but impairs immune responses

The programmed, stepwise acquisition of immunocompetence that marks the development of the fetal immune response proceeds during a period when both T cell receptor and immunoglobulin (Ig) repertoires exhibit reduced junctional diversity due to physiologic terminal deoxynucleotidyl transferase (TdT) insufficiency. To test the effect of N addition on humoral responses, we transplanted bone marrow from TdT-deficient (TdT−/−) and wild-type (TdT+/+) BALB/c mice into recombination activation gene 1-deficient BALB/c hosts. Mice transplanted with TdT−/− cells exhibited diminished humoral responses to the T-independent antigens α-1-dextran and (2,4,6-trinitrophenyl) hapten conjugated to AminoEthylCarboxymethyl-FICOLL, to the T-dependent antigens NP19CGG and hen egg lysozyme, and to Enterobacter cloacae, a commensal bacteria that can become an opportunistic pathogen in immature and immunocompromised hosts. An exception to this pattern of reduction was the T-independent anti-phosphorylcholine response to Streptococcus pneumoniae, which is normally dominated by the N-deficient T15 idiotype. Most of the humoral immune responses in the recipients of TdT−/− bone marrow were impaired, yet population of the blood with B and T cells occurred more rapidly. To further test the effect of N-deficiency on B cell and T cell population growth, transplanted TdT-sufficient and -deficient BALB/c IgMa and congenic TdT-sufficient CB17 IgMb bone marrow were placed in competition. TdT−/− cells demonstrated an advantage in populating the bone marrow, the spleen, and the peritoneal cavity. TdT deficiency, which characterizes fetal lymphocytes, thus appears to facilitate filling both central and peripheral lymphoid compartments, but at the cost of altered responses to a broad set of antigens