Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2-6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2-6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT.
In the past decade, many studies have highlighted the role of metabotropic glutamate receptor subtype 5 (mGlu5) modulators in attenuating alcohol-related biological effects such as alcohol consumption, alcohol-seeking and relapse-like behaviors. Taken together, these findings suggest that pharmacological agents acting at mGlu5 could be promising tools in curbing inebriation. mGlu5s are present abundantly in brain regions known to be involved in emotion regulation, motivation and drug administration. On a cellular level, they are primarily located at the postsynaptic part of the neuron where the receptor is functionally linked to various downstream proteins that are involved in cell signaling and gene transcription that mediate the alcohol-induced neuroplasticity. As well, the discovery of a functional link between mGlu5 and a specific isozyme, Protein Kinase C epsilon (PKCε) in mediating the attenuating effects of selective negative allosteric modulators of mGlu5 such as methyl- 6(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) has sparked interesting speculations. In this article, we shall review the following: the effects of acute and chronic alcohol intake on mGlu5 signaling; the effects of mGlu5 ligands on alcohol-related neurobehavioral changes that are currently being studied both at pre-clinical and clinical stages; and the mechanisms underlying the pharmacological effects of these drugs.
Background Low ionized calcium (ICa) is prevalent in critical care patients. It is poorly detected by the popular indirect method, which corrects serum total calcium (TCa) for change in albumin. That correction (cTCa) ignores any concomitant change in the anion-complexed fraction of TCa. We tested whether the diagnosis of low ICa can be improved by further correcting for calcium complexation, represented by the anion gap (AG) or its components—sodium, chloride, and total carbon dioxide (tCO2). Methods We retrospectively studied all patients in our intensive care units between 2009 and 2011 with ICa measured on arterial (n = 310) or venous (n = 462) gas panels within 19 min of a comprehensive chemistry panel. Logistic models to predict low ICa and linear models to estimate ICa were derived in the arterial group and validated in the venous group, using either AG (AG model) or its components (Ion model) as predictors, adjusted for TCa and albumin. Results AG and its set of components were each highly significant independent predictors of low ICa. On validation, the logistic Ion model was better than the logistic AG model (ROC curve area ± SE: 0.92 ± 0.02 vs 0.89 ± 0.02; P = 0.008), which, in turn, was far better than cTCa (0.81 ± 0.03; P = 0.0006); the hypocalcemia rates predicted by the models showed good fit with the observed rates. Linear estimates of ICa were too imprecise for clinical use. Conclusions The adjustment of TCa for AG or for sodium, chloride, and tCO2 markedly improves the diagnosis of low ICa. This finding may be useful in guiding ICa testing.
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