AIDS patients have increased surfactant protein D but normal mannose binding lectin levels in lung fluid.

BACKGROUND: Surfactant protein D (SP-D) and Mannose Binding Lectin (MBL) are collectins that have opsonic and immunoregulatory functions, are found in lung fluid and interact with the human immunodeficiency virus (HIV). We compared collectin levels in lung fluid and serum from HIV infected and normal subjects to determine if alterations in lung collectin levels were associated with HIV infection and might result in increased susceptibility to other pulmonary infections. METHODS: Blood and bronchoalveolar lavage samples were collected from 19 HIV-infected individuals and 17 HIV-uninfected individuals, all with normal chest X ray at time of study. HIV viral loads and peripheral blood CD4+ T cell counts were measured in all subjects. SP-D was measured in lung fluid, and MBL in both lung fluid and serum. RESULTS: SP-D levels were not significantly different in lung fluid from HIV-uninfected (median 406.72 ng/ml) and HIV-infected individuals with high CD4 count (CD4 >200) (median 382.60 ng/ml) but were elevated in HIV-infected individuals with low CD4 count (median 577.79 ng/ml; Kruskall Wallis p < 0.05). MBL levels in serum were not significantly different between HIV-uninfected and HIV-infected individuals (median 1782.70 ng/ml vs 2639.73 ng/ml) and were not detectable in lung fluid. CONCLUSION: SP-D levels are increased in lung fluid from AIDS patients but not in patients with early HIV infection. MBL levels are not altered by HIV infection or AIDS. There is no evidence that altered pulmonary collectin levels result in susceptibility to infection in these patients

Modeling Phased Reduction of Distortionary Policies in the U.S. Wheat Market under Alternative Macroeconomic Environments

Throughout much of the developed world, macroeconomic policies afforded a unique period of macroeconomic stability in the two decades following World War II. As a result, concern regarding the macroeconomic linkages with food and agricultural systems largely disappeared. In the early 1970s, with the major changes in monetary policies and central bank behavior, macroeconomic linkages were once again recognized as prime factors complicating the performance of the agricultural and food systems. The roller coaster ride that agriculture experienced over the 1970s and 1980s has been significantly influenced by macroeconomic and international linkages (Rausser et al., 1966). Agriculture\u27s prosperous condition in the 1970s was followed by a recession in the 1980s. This more recent history stands in sharp contrast to the basic stability of the 1950s and 1960s. It is also important to recall that this roller coaster experience of the 1970s and 1980s is not unprecedented. For example, the period from 1900 through 1950 is surprisingly similar to the 1970s; and the late 1920s through the 1930s have some basic characteristics of the 1980s

Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION)

Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility.This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.2014-004687-37; Pre-results

The role of serum- and glucocorticoid kinase in the hormonal control of sodium transport in pulmonary epithelia

In the hormonal control of sodium transport in the lung via glucocorticoids there is substantial evidence that supports a central role for serum- and glucocorticoid-kinase(SGK1). The activity of this kinase is dependent upon phosphorylation of two distinct residues by the target of rapamycin complex 2 (TORC2) and phosphoinositidedependent Kinase 1 (PDK1), both of which are dependent upon Phosphoinositide-3-Kinase (PI3K). However, SGK1 knockout mice do not display any pulmonary abnormalities. Thus the role that SGK1 plays is not fully understood. In this thesis I have explored the role of this kinase in dexamethasone-induced ENaC activity in the H441 human bronchiolar cell model. Dexamethasone-deprived cells do not display ENaC activity as there is no amiloride sensitive current in these cells. Groups of dexamethasone-treated H441 cells do display ENaC activity; however single cells do not display ENaC activity despite displaying an increase in current. Thus cell-cell contact is vital to the development of amiloride sensitivity. SGK1 activity does not mimic the electrophysiological effects of dexamethasone-stimulation as there is no amiloride sensitivity seen after ~3 hours despite a clear increase in SGK1 activity. Furthermore after ~24 hours stimulation, there is a clear amiloride sensitive current although SGK1 activity is comparable to that of dexamethasone-deprived cells. These findings further question whether SGK1 is required for dexamethasone-evoked ENaC activity. Inhibition of PI3K, TORC2 and SGK1 abolished ENaC activity. However inhibition of TORC1 had no effect upon dexamethasone induced ENaC activity. Thus demonstrates that the maintenance of glucocorticoid induced ENaC activity, in pulmonary epithelium, is dependent upon the PI3K-TORC2-SGK1 signalling pathway. Furthermore PI3K plays a permissive, but critical role as its activity is required for SGK1 activity. However without SGK1 activity dexamethasone induced ENaC activity cannot be maintained.EThOS - Electronic Theses Online ServiceGeorge John and Sheilah Livanos Charitable TrustGBUnited Kingdo

C3b/iC3b Deposition on Streptococcus pneumoniae Is Not Affected by HIV Infection

Streptococcus pneumoniae is a common cause of infection in both HIV positive patients and those with complement deficiencies. We hypothesised that HIV positive individuals might exhibit reduced opsonisation of pneumococcus with complement due to reduced levels of S. pneumoniae specific IgG. We discovered no difference in C3 deposition on S. pneumoniae between HIV positive or negative individuals, and furthermore C3 deposition remained unchanged as HIV progressed towards AIDS. We found no correlation between C3 deposition on S. pneumoniae and CD4 cell count in HIV infected individuals. Hence we have demonstrated no failure of complement immunity in HIV positive patients

Stakeholder views on the acceptability of human infection studies in Malawi.

BACKGROUND: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMICs) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMICs. METHODS: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members, and district health government officials. RESULTS: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to the safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example, balancing equity, safety, and relevance in inclusion criteria. CONCLUSIONS: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out

A health systems approach to critical care delivery in low-resource settings: a narrative review

There is a high burden of critical illness in low-income countries (LICs), adding pressure to already strained health systems. Over the next decade, the need for critical care is expected to grow due to ageing populations with increasing medical complexity; limited access to primary care; climate change; natural disasters; and conflict. In 2019, the 72nd World Health Assembly emphasised that an essential part of universal health coverage is improved access to effective emergency and critical care and to “ensure the timely and effective delivery of life-saving health care services to those in need”. In this narrative review, we examine critical care capacity building in LICs from a health systems perspective. We conducted a systematic literature search, using the World Heath Organisation (WHO) health systems framework to structure findings within six core components or “building blocks”: (1) service delivery; (2) health workforce; (3) health information systems; (4) access to essential medicines and equipment; (5) financing; and (6) leadership and governance. We provide recommendations using this framework, derived from the literature identified in our review. These recommendations are useful for policy makers, health service researchers and healthcare workers to inform critical care capacity building in low-resource settings

Global hydrodynamic analysis of the molecular flexibility of galactomannans

In the past, intrinsic viscosity and sedimentation velocity analyses have been used separately to assess the conformation and flexibility of guar and locust bean gum galactomannans based on worm-like chain and semi-flexible coil models. Publication of a new global method combining data sets of both intrinsic viscosity and sedimentation coefficient with molecular weight, and minimising a target (error) function now permits a more robust analysis. Using this approach, values for the persistence length of (10 ± 2) nm for guar and (7 ± 1) nm for locust bean gum are returned if the mass per unit length ML is floated as a variable. Using a fixed mass per unit length based on the known compositional data of each galactomannan yields a similar value for Lp in both cases, (8 ± 1) nm for guar and (9 ± 1) nm for locust bean gum, with combined set of data yielding (9 ± 1) nm: within experimental error the flexibilities of both galactomannans are very similar. © 2007 Elsevier Ltd. All rights reserved