LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation

The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.     

Secondary biogenic amine deficiencies: genetic etiology,therapeutic interventions,and clinical effects

neurogenetics - Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that...     

Neuronal PINCH is Regulated by TNF-�� and is Required for Neurite Extension

During HIV infection of the CNS, neurons are damaged by viral proteins, such as Tat and gp120, or by inflammatory factors, such as TNF-α, that are released from infected and/or activated glial cells. Host responses to this damage may include the induction of survival or repair mechanisms. In this context, previous studies report robust expression of a protein called particularly interesting new cysteine histidine-rich protein (PINCH), in the neurons of HIV patients’ brains, compared with nearly undetectable levels in HIV-negative individuals (Rearden et al., J Neurosci Res 86:2535–2542, 2008), suggesting PINCH’s involvement in neuronal signaling during HIV infection of the brain. To address potential triggers for PINCH induction in HIV patients’ brains, an in vitro system mimicking some aspects of HIV infection of the CNS was utilized. We investigated neuronal PINCH expression, subcellular distribution, and biological consequences of PINCH sequestration upon challenge with Tat, gp120, and TNF-α. Our results indicate that in neurons, TNF-α stimulation increases PINCH expression and changes its subcellular localization. Furthermore, PINCH mobility is required to maintain neurite extension upon challenge with TNF-α. PINCH may function as a neuron-specific host-mediated response to challenge by HIV-related factors in the CNS.     

Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice.

Many antidepressant drugs interact with sigma receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans. sigma Receptors are localized in brain regions affected in depression, further strengthening the hypothesis that they represent logical drug development targets. In this study, two novel sigma receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for sigma receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The sigma receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that sigma receptor agonists represent a possible new class of antidepressant medication.     

Feeding Practices and Growth in Yemeni Children

A nutritional survey in the Tihama region of Yemen allowed an analysis of the relationship between infant feeding practices and the growth of children 3-23 months of age. The survey was conducted in 1979 on a representative sample of 364 preschool children 3-23 months of age. After adjustment for demographic and socioeconomic factors, breast feeding was found to be associated with higher weight-for-length and weight-for-age. The strongest beneficial effect of breast feeding on weight-for-length was seen at 3-6 months, a weaker effect at 7-12 months, and essentially no effect over 12 months of age. A higher weight-for-age was seen in breast-fed infants 3-6 months of age only. Introducing other foods was associated with higher weight-for-length only in children 13-23 months of age. Neither breast feeding nor introducing other foods was associated with length-for-age. Infant feeding practices appear to be associated with weight gain, but not linear growth in Yemeni infants.     

Multivariate spatial models for event data

This paper describes how estimates made for event rates in small areas may be enhanced through spatial modelling of the data - taking the geographical location of each area into account - and through the addition of further information from each area. In particular we consider the use of spatial models to predict more than one outcome simultaneously. This is done by writing the spatial model as a multi-level model and subsequently enhancing this to encompass a multivariate data structure; estimates are obtained using iterative generalized least squares in the software package MLwiN. The example given considers mortality due to two causes--neoplasms and circulatory disease--in 143 postcode sectors in Greater Glasgow Health Board, Scotland. In addition, a measure of socio-economic deprivation is available for each area. Correlations between causes within areas, between areas within causes and between areas and causes are quantified, as are the relative contributions of the heterogeneous and spatial parts of the model. The results suggest a tendency for there to be pockets with high mortality rates due to neoplasms, whilst mortality due to circulatory disease follows a much smoother pattern. After taking deprivation into account, the spatial component accounts for just 19 per cent of the variation in the mortality due to neoplasms in Greater Glasgow but 66 per cent of the mortality due to circulatory disease.     

Observations and recommendations for assessing patient satisfaction in a primary care setting using a previously validated questionnaire

Within the rapidly changing climate of primary care, there is an increasing need to evaluate the reactions of patients to real and proposed changes in practice. There are a number of methodologies, both qualitative and quantitative which have been employed to do this. This article presents the methodological problems which may be encountered in evaluating patients' opinions and attitudes in a primary care setting. We begin by discussing the issues which need evaluation, then describe the research process of a recent case study which aimed to evaluate patient satisfaction using a previously validated survey instrument, including the modifications which had to be made to overcome the problems of research in a real life practice setting. We then discuss the strengths and weaknesses of applying different methodological instruments within a primary care setting, and propose a mixed methodological framework as a template for future research which combines the strengths of both large scale survey and small scale qualitative methods to give more insight into the concerns and beliefs of patients as changes occur within their local practice.     

The effect of neonatal hyperbilirubinemia on the measurement of plasma creatinine

Bilirubin interferes with the measurement of plasma creatinine by the kinetic colorimetric Jaffe reaction, the method currently used by many hospital laboratories. The purpose of the present study was to evaluate the influence of unconjugated bilirubin on the measurement of plasma creatinine by the AutoAnalyzer Jaffe end point method. This colorimetric method is slower but more precise and accurate in the range of 0.25 to 0.5 mg/dl. We found that bilirubin from jaundiced neonates and from stock solutions did not affect the determination of creatinine chromogen in plasma or in saline, even at concentrations as high as 25 mg/dl. We conclude that the use of the Jaffe end point AutoAnalyzer method with a blank run before each sample will provide an accurate measurement of creatinine in the plasma of the neonate with unconjugated hyperbilirubinemia.     

A simple estimate of glomerular filtration rate in full-term infants during the first year of life

An estimate of glomerular filtration rate has been derived for children from body length (L, in centimeters) and plasma creatinine (Pcr, in milligrams per deciliter): GFR = 0.55 L/Pcr. The near universality of this estimate in children led us to seek a similar formula for estimating GFR in full-term infants during the first year of life. We measured Pcr in 137 healthy infants and performed creatinine clearance (Ccr) studies in 63 of them aged greater than or equal to 5 days. Beyond the first week, Pcr averaged 0.39 +/- 0.01 (0.10 SD) mg/dl. The estimate of GFR from 0.55 L/Pcr overestimated Ccr by 24% (P less than 0.001). Based on the calculation of a new constant from Ccr X Pcr/L, GFR was more accurately estimated from 0.45 L/Pcr (mean difference of Ccr - 0.45 L/Pcr = -0.4 +/- 3.7 (SE) ml/min X 1.73 m2) in full-term infants between 1 and 52 weeks of age. Because the constant 0.45 and Pcr do not change significantly during this period, GFR can be approximated at the bedside from body length of the healthy full-term infant (GFR = 0.45 L/0.39 = 1.1 L).