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Hingham MA 02043
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RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia. - Pharmacogenomics
Variation in terms of outcome and toxic side effects of treatment exists among acute myeloid leukemia (AML) patients on chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Candidate Ara-C metabolizing gene expression in primary AML cells is proposed to account for this variation.Ex vivo Ara-C sensitivity was determined in primary AML samples using MTT assay. mRNA expression of candidate Ara-C metabolizing genes were evaluated by RQPCR analysis. Global gene expression profiling was carried out for identifying differentially expressed genes between exvivo Ara-C sensitive and resistant samples.Wide interindividual variations in ex vivo Ara-C cytotoxicity were observed among samples from patients with AML and were stratified into sensitive, intermediately sensitive and resistant, based on IC50 values obtained by MTT assay. RNA expression of deoxycytidine kinase (DCK), human equilibrative nucleoside transporter-1 (ENT1) and ribonucleotide reductase M1 (RRM1) were significantly higher and cytidine deaminase (CDA) was significantly lower in ex vivo Ara-C sensitive samples. Higher DCK and RRM1 expression in AML patient's blast correlated with better DFS. Ara-C resistance index (RI), a mathematically derived quotient was proposed based on candidate gene expression pattern. Ara-C ex vivo sensitive samples were found to have significantly lower RI compared with resistant as well as samples from patients presenting with relapse. Patients with low RI supposedly highly sensitive to Ara-C were found to have higher incidence of induction death (p = 0.002; RR: 4.35 [95% CI: 1.69-11.22]). Global gene expression profiling undertaken to find out additional contributors of Ara-C resistance identified many apoptosis as well as metabolic pathway genes to be differentially expressed between Ara-C resistant and sensitive samples.This study highlights the importance of evaluating expression of candidate Ara-C metabolizing genes in predicting ex vivo drug response as well as treatment outcome. RI could be a predictor of ex vivo Ara-C response irrespective of cytogenetic and molecular risk groups and a potential biomarker for AML treatment outcome and toxicity. Original submitted 22 December 2014; Revision submitted 9 April 2015.
Effects of Rapid Intravenous Rehydration in Children With Mild-to-Moderate Dehydration. - Pediatric emergency care
New guidelines for "rapid or ultrarapid" intravenous rehydration are being developed in different emergency departments. These new guidelines propose a faster administration of fluids and electrolytes than in traditional protocols. However, there is still insufficient evidence to establish a standard protocol.Our objective was to determine the effects of an outpatient rapid intravenous rehydration regimen based on the administration of 0.9% saline + 2.5% dextrose, at a rate of 20 mL/kg per hour for 2 hours, in children with mild-to-moderate isonatremic dehydration resulting from acute gastroenteritis.We performed a 2-institution, prospective, observational, descriptive study. Eighty-three patients were included in the study. All patients underwent a first evaluation, including physical examination, laboratory tests, and assessment of clinical degree of dehydration. After this initial evaluation, all children received our intravenous rehydration regimen. A second evaluation including the same items as in the first one was made after in all the children.Intravenous rehydration was successful in 69 patients (83.1%). It failed in 14 patients (16.8%), who required hospitalization because of persistent vomiting in 9 patients and poor general appearance in 5 patients. After intravenous rehydration, we observed a statistically significant decrease in the levels of ketonemia and uremia and in the Gorelick scale score. However, no significant changes were observed in sodium, chloride, potassium, and osmolarity values.We conclude that, in children with mild-to-moderate dehydration, the administration of 20 mL/kg per hour for 2 hours of 0.9% saline solution + 2.5% glucose improved clinical scores and may be used as an alternative and safe way for intravenous rehydration.
Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance. - PloS one
There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.
Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice. - Molecular brain
Current evidence suggests a central role for autophagy in many neurodegenerative diseases including Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Furthermore, it is well admitted that inflammation contributes to the progression of these diseases. Interestingly, crosstalks between autophagy and inflammation have been reported in vitro and at the peripheral level such as in Crohn's disease. However, the impact of systemic inflammation on autophagic components in the brain remains to be documented. Therefore, this study monitored autophagy markers after acute and chronic lipopolysaccharide (LPS)-induced inflammatory stress in mice.We showed that acute inflammation, 24 h post-intraperitoneal 10 mg/kg LPS, substantially increased cytokine production (Interleukin(IL)-1Î², Tumor necrosis factor (TNF)-Î± and IL-6), decreased the levels of autophagy markers (Beclin-1, p62 and LC3 II) and reduced p70S6K activation in cortex and hippocampus. In hippocampus, IL-1Î² levels and LC3 II expression were positively and highly correlated and a negative correlation was noted between TNF-Î± levels and p70S6K activation. Chronic inflammation by injection of 0.5 mg/kg LPS every three days during three months led to a moderate IL-1Î² production and decreased TNF-Î± levels. Interestingly, Beclin-1 and LC3 II levels decreased while those of p62 increased. Cortical IL-1Î² levels positively correlated with Beclin-1 and LC3 II and on the contrary inversely correlated with p62.The present study is the first showing links between IL-1Î²-mediated inflammation and autophagy in the brain. It could open to new therapeutic strategies in brain diseases where regulation impairment of inflammation and autophagy progress with the severity of diseases.
Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice. - Journal of neuroinflammation
In recent years, studies have sought to understand the mechanisms involved in the alteration of autophagic flux in Alzheimer's disease (AD). Alongside the recent description of the impairment of lysosomal acidification, we wanted to study the relationships between inflammation and autophagy, two physiological components deregulated in AD. Therefore, a longitudinal study was performed in APPswePS1dE9 transgenic mice at three, six and twelve months of age.Autophagic markers (Beclin-1, p62 and LC3) and the activation of mammalian Target of Rapamycin (mTOR) signaling pathway were quantified by western blot. Cytokine levels (IL-1Î², TNF-Î± and IL-6) were measured by ELISA. Transmission electron microscopy was performed to detect autophagic vacuoles. Mann-Whitney tests were used to compare wild-type (WT) versus APPswePS1dE9 mice. Longitudinal changes in parameters were analyzed with a Kruskal-Wallis test followed by a post-hoc Dunn's test. Correlation between two parameters was assessed using a Spearman test.Compared to 12-month old WT mice, 12-month old APPswePS1dE9 mice had higher levels of IL-1Î² and TNF-Î±, a greater inhibition of the mTOR signaling pathway and lower levels of Beclin-1 expression both in cortex and hippocampus. Regarding the relationship of the various parameters in 12-month old APPswePS1dE9 mice, Beclin-1 rates were positively correlated with IL-1Î² and TNF-Î± levels. And, on the contrary, TNF-Î± levels were inversely correlated with the levels of mTOR activation. Altogether, these results suggest that inflammation could induce autophagy in APPswePS1dE9 mice. However, these transgenic mice displayed a large accumulation of autophagic vesicles within dystrophic neurons in cortex and hippocampus, indicating a terminal failure in the autophagic process.This first demonstration of relationships between inflammation and autophagy in in vivo models of AD should be taken into account in new therapeutic strategies to prevent inflammation and/or stimulate autophagy in advanced neurodegenerative process such as AD.
Involvement of interleukin-1Î² in the autophagic process of microglia: relevance to Alzheimer's disease. - Journal of neuroinflammation
Autophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer's Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined.Here, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (AÎ²42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls' test.AÎ²42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1Î², TNF-Î±, and IL-6) or IL-1Î² alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1Î² in the induction of autophagy in tri-cultures in the presence or absence of AÎ²42. However, the vulnerability of the autophagic process in purified microglia to IL-1Î² was prevented by AÎ²42.These findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1Î² in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.
Tick-borne encephalitis associated with consumption of raw goat milk, Slovenia, 2012. - Emerging infectious diseases
Tick-borne encephalitis (TBE) developed in 3 persons in Slovenia who drank raw milk; a fourth person, who had been vaccinated against TBE, remained healthy. TBE virus RNA was detected in serum and milk of the source goat. Persons in TBE-endemic areas should be encouraged to drink only boiled/pasteurized milk and to be vaccinated.
Reliability and validity of the Malay translated version of diabetes quality of life for youth questionnaire. - Malaysian family physician : the official journal of the Academy of Family Physicians of Malaysia
Many studies reported poorer quality of life (QoL) in youth with diabetes compared to healthy peers. One of the tools used is the Diabetes Quality of Life for Youth (DQoLY) questionnaire in English. A validated instrument in Malay is needed to assess the perception of QoL among youth with diabetes in Malaysia.To translate the modified version, i.e., the DQoLY questionnaire,into Malay and determine its reliability and validity.Translation and back-translation were used. An expert panel reviewed the translated version for conceptual and content equivalence. The final version was then administered to youths with type 1 diabetes mellitus from the universities and Ministry of Health hospitals between August 2006 and September 2007. Reliability was analysed using Cronbach's alpha, while validity was confirmed using concurrent validity (HbA1c and self-rated health score).A total of 82 youths with type 1 diabetes (38 males) aged 10-18 years were enrolled from eight hospitals. The reliability of overall questionnaire was 0.917, and the reliabilities of the three domains ranged from 0.832 to 0.867. HbA1c was positively correlated with worry (p=0.03). The self-rated health score was found to have significant negative correlation with the "satisfaction" (p=0.013) and "impact" (p=0.007) domains.The Malay translated version of DQoLY questionnaire was reliable and valid to be used among youths with type 2 diabetes in Malaysia.
Role of minimal residual disease monitoring in acute promyelocytic leukemia treated with arsenic trioxide in frontline therapy. - Blood
Data on minimal residual disease (MRD) monitoring in acute promyelocytic leukemia (APL) are available only in the context of conventional all-trans retinoic acid plus chemotherapy regimens. It is recognized that the kinetics of leukemia clearance is different with the use of arsenic trioxide (ATO) in the treatment of APL. We undertook a prospective peripheral blood RT-PCR-based MRD monitoring study on patients with APL treated with a single agent ATO regimen. A total of 151 patients were enrolled in this study. A positive RT-PCR reading at the end of induction therapy was significantly associated on a multivariate analysis with an increased risk of relapse (relative risk = 4.9; P = .034). None of the good risk patients who were RT-PCR negative at the end of induction relapsed. The majority of the relapses (91%) happened within 3 years of completion of treatment. After achievement of molecular remission, the current MRD monitoring strategy was able to predict relapse in 60% of cases with an overall sensitivity and specificity of 60% and 93.2%, respectively. High-risk group patients and those that remain RT-PCR positive at the end of induction are likely to benefit from serial MRD monitoring by RT-PCR for a period of 3 years from completion of therapy.
Long-term changes in food consumption trends in overweight children in the HIKCUPS intervention. - Journal of pediatric gastroenterology and nutrition
Energy intake is a major contributor to energy imbalance and is a key modifiable factor for successful treatment of obesity. Long-term changes in dietary intake from pediatric obesity treatment programs are rarely reported. The aim of this study was to describe the changes in food intake of children from all intervention groups from baseline to 2-year follow-up after a 6-month obesity intervention.Overweight children (n = 160, 5-9 years), 58% girls and body mass index z score (mean Â± SD) 2.89 Â± 0.79, were recruited to the Hunter Illawarra Kids Challenge using the Parent Support randomized controlled trial. Dietary intake was reported by parents for children at baseline and 2-year follow-up (n = 87) using a food frequency questionnaire. Linear mixed models were used to determine differences by time.Parents reported decreases in total energy (total kcal, kcal/kg), child percentage of total energy from energy-dense, nutrient-poor foods (sweetened drinks, potato crisps, sweets, and carry-out foods) from 42% Â± 1.0% at baseline to 34.8% Â± 1.0% at 2 years (P < 0.001), with an increase in percentage of energy from nutrient-dense foods (fruits, vegetables, dairy, breads, and cereals) from 57% Â± 0.9% at baseline to 65% Â± 1.0% at 2 years (P < 0.001).This is the only one of a few studies that report dietary data of overweight children who participated in a treatment program with long-term follow-up. It provides evidence that improvements in food intake can be sustained up to 2 years through decreased consumption of energy-dense, nutrient-poor foods, particularly sweetened drinks, and increased consumption of core foods following an intervention.
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