Residual effects of intra-articular betamethasone and triamcinolone acetonide in an equine acute synovitis model.

BACKGROUND: Intra-articular (IA) corticosteroids are regularly used in equine athletes for the control of joint inflammation. OBJECTIVES: The goal of this study was to use an acute synovitis inflammation model to determine the residual effects of IA betamethasone and triamcinolone acetonide on various inflammatory parameters and lameness. STUDY DESIGN: Crossover randomised trial. METHODS: Five mixed-breed, 2-year-old horses were randomly allocated to an IA treatment of the radiocarpal joint with 9 mg of either betamethasone or triamcinolone acetonide. Two weeks following treatment, horses were injected with 1 µg of lipopolysaccharide (LPS) diluted in 1 ml of saline. Following LPS injection, horses were crossed-over and both sets of injections were repeated after a washout period. Blood samples were collected at multiple time points for mRNA analysis, as well as serum amyloid A (SAA) and cortisol determination. At each time point, lameness was also subjectively scored. Additional injections with saline-only or LPS-only (twice) were conducted as negative and positive controls, respectively. Two-way repeated measures analysis of variance was used to analyse all data. RESULTS: Corticosteroid-only treatments result in significant mRNA expression differences, as well as significant and prolonged cortisol suppression. Following LPS injection, there was a residual treatment effect with triamcinolone evidenced by a significant treatment effect on IL-6 and PTGS1 (cyclooxygenase-1), lameness, SAA and cortisol concentrations, while only IL-6 expression was affected by betamethasone. MAIN LIMITATIONS: The acute synovitis model used here results in significant inflammation and is not representative of the low-grade inflammation seen with typical joint disease and residual anti-inflammatory effects may be more profound in naturally occurring joint disease. CONCLUSIONS: Current regulatory guidelines may be insufficient if the concern is residual anti-inflammatory effects. Additionally, intra-articular corticosteroid administration is not without risk, as evidenced by a significant suppression of serum cortisol concentration and, as such, the benefits of their administration should be weighed against those risks.

The intersection of race and socioeconomic status is associated with inflammation patterns during pregnancy and adverse pregnancy outcomes.

BACKGROUND: Preterm birth rates are higher among individuals of lower socioeconomic status and non-White race, which is possibly related to life-course stressors. It is important to understand the underlying mechanisms of these health disparities, and inflammation is a possible pathway to explain the disparities in birth outcomes. OBJECTIVE: In this study, we aimed to determine whether patterns of inflammation differed by maternal race and socioeconomic status. STUDY DESIGN: Seven hundred and forty-four participants in a multi-site, prospective study of pregnancy and birth outcomes provided biological and psychological data between 12'0-20'6 weeks gestation. Participants with recent infection, fever, antibiotics or steroid treatment were excluded. Cytokines including INFÉ£, IL-10, IL-13, IL-6, IL-8, and TNFα, and the acute phase protein CRP were measured in serum and values and were log-transformed for normality when appropriate, and a non-orthogonal rotation (Oblimid) was performed to allow the extracted factor to inter-correlate. IFNγ, IL-8, IL-10, IL-6, TNF-a, and IL-13 loaded onto Inflammatory Factor 1 (IF-1), while CRP and IL-6 loaded onto Inflammatory Factor 2 (IF-2). Race and education were collected via self-report during an in-person study visit. Multivariable models were used to determine the association of race and SES with IF-1 and IF-2 during the second trimester, and a mediation model was used to examine if inflammation is on the causal pathway. Models were adjusted for study site, prenatal age, pre-pregnancy BMI, smoking during pregnancy, and gestational age at the time of blood collection. RESULTS: Six hundred and five participants were included in our final analysis, with 61.2% of low or moderate SES, and 35.5% identifying as a person of color (POC). Identifying as a POC, being of low and moderate SES, and being both low-SES and POC or moderate-SES and POC were associated with higher odds of preterm birth and lower birth weight percentile infants. Low SES POC participants had significantly higher IF-1 and IF-2 scores when compared to high-SES White participants. Additionally, higher IF-1 and IF-2 were associated with shorter gestation. In the mediation analysis, we observed a significant direct effect of race/SES on preterm birth; however, the results did not support an indirect pathway where IF-1 or IF-2 acted as mediators. CONCLUSION: Maternal race and SES are significantly associated with inflammatory biomarkers during pregnancy, and when race and SES are considered in combination, they are stronger predictors of adverse pregnancy outcomes than when evaluated separately.

Using principal component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes.

OBJECTIVE: Inflammation as a risk factor for preterm birth is well-established. The primary objective of this analysis was to examine whether individual cytokines versus a composite indicator of mid-pregnancy inflammation are significantly associated with risk for adverse birth outcomes. STUDY DESIGN: A multi-site prospective study was conducted in a socio-demographically diverse cohort of 610 pregnant participants. At a study visit between 12 and 20 6/7 weeks' gestation, low-grade inflammation was measured via log-transformed serum concentrations of the biomarkers IFN-γ, IL-10, IL-13, IL-6, IL-8, TNF-α, and CRP. Principal component analysis (PCA) was used to identify underlying dimensions of inflammatory activity from the seven biomarkers measured. Gestational age and birth weight at delivery were obtained from medical chart review. The associations between inflammatory profiles and birth outcomes were assessed via linear and logistic regression models. Results were compared with those from individual inflammatory biomarkers, and model fit was assessed using Akaike's Information Criterion (AIC). RESULTS: Principal component analysis analysis yielded a two-factor solution, with the first factor (IF1) composed of IL-8, IL-10, IL-13, IFN-É£, and TNF-α, and the second factor (IF2) containing IL-6 and CRP. When adjusted for race, education, BMI, smoking status, gestational age at time of blood draw, and study site, a one standard deviation (SD) increase in IF1 remained significantly associated with a decrease in standardized gestational age (ß = -.13, 95% CI: -.21, -.05) and an increase in odds of preterm delivery (OR = 1.46, 95% CI: 1.13, 1.88) (Table 3). A one SD increase in IF2 was similarly associated with a decrease in standardized gestational age at delivery (ß = -.13, 95% CI: -.23, -.04) and an increase in odds of preterm delivery (OR: 1.46, 95% CI: 1.04, 2.05). Neither IF1 nor IF2 was associated with measures of fetal growth. AIC identified that IL-6 was a slightly better fit for length of gestation compared to either composite measure, though all performed similarly. CONCLUSION: Independent of known sociodemographic risk factors, an elevated mid-pregnancy inflammatory profile was associated with a nearly 50% increase in odds of preterm delivery. The composite performed similarly to IL-6. These results suggest that maternal low-grade inflammation is a risk factor for preterm delivery, and that mid-pregnancy inflammatory biomarkers may be useful in predicting risk for preterm delivery.

Prospective association of maternal immune pro-inflammatory responsivity and regulation in pregnancy with length of gestation.

PROBLEM: The immune system represents a leading pathway of interest in the pathophysiology of preterm birth. The majority of human clinical studies interrogating this pathway have utilized circulating immune biomarkers; however, these concentrations typically reflect only basal production but not key functional properties of the immune system, particularly variation in the pro-inflammatory response to antigen challenge and the regulation of this response. Thus, in this study, we utilized an ex vivo stimulation protocol that quantifies these processes, and we examined their prospective association with the gestation length and risk of preterm birth. METHOD OF STUDY: Immune responsiveness and regulation were assessed in 128 pregnant women in mid-gestation using an ex vivo stimulation protocol. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1ß in response to antigen stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of stimulated cytokine response upon co-incubation with increasing dexamethasone concentrations (ie, glucocorticoid receptor resistance; GRR). RESULTS: Higher maternal GRR, indicating impaired regulation of the pro-inflammatory response, was significantly and independently associated with shorter gestational length (ß = -0.42, p = .0091) and a 3.0-fold increase in risk for preterm birth (OR = 3.01, 95% CI = 1.17-7.70, p = .0218). Basal circulating IL-6 and TNF-α were not associated with either outcome. CONCLUSION: The association of maternal GRR with length of gestation and preterm birth risk suggests that the processes represented by this measure-maternal pro-inflammatory propensity and immune regulation-may provide further mechanistic insight into the pathophysiology of preterm birth.

Are personality traits associated with smoking and alcohol use prior to and during pregnancy?

Cigarette smoking and alcohol consumption during pregnancy can have detrimental effects on the developing fetus, including fetal alcohol syndrome and low birth weight. Surprisingly little is known about the association of personality traits with smoking and alcohol consumption in the specific subpopulation of pregnant women. This study analyzed data from a geographically diverse sample of 603 pregnant women, aged 18 years and older, who provided information regarding their smoking and drinking habits before and during pregnancy. We compared women who consumed alcohol or smoked cigarettes before pregnancy with women who quit or continued smoking or drinking during pregnancy. Associations between personality and maladaptive behaviors prior to and during pregnancy were modeled using logistic regression. The study revealed that women who scored high on openness to experience were significantly more likely to continue alcohol consumption during pregnancy (OR = 1.07, 95% CI 1.01, 1.14, p = .02). This association was maintained after adjusting for potential confounds. This study demonstrated a significant relationship between personality traits and women's likelihood of continued alcohol consumption prior to and during pregnancy. Understanding personality-based determinants of health-detrimental behavior is important in order to design interventions that aim at decreasing rates of maladaptive health behaviors among pregnant women.

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or with TP53 defect, with BTK and phospholipase C gamma 2 (PLCG2) mutations representing the predominant mechanisms conferring secondary ibrutinib resistance. To understand the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment, an ultra-deep next-generation sequencing analysis of 30 recurrently mutated genes was performed on sequential samples of 20 patients, collected before and during single-agent ibrutinib treatment. Mutations in the SF3B1, MGAand BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in posttreatment samples. Besides the canonical mutations, four novel BTK mutations and three previously unreported PLCG2 variants were identified. BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR and were detectable on average 10.5 months before clinical relapse. With a median follow-up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease progression based on clinical and/or laboratory features. In conclusion, subclonal heterogeneity, dynamic clonal selection and various patterns of clonal variegation were identified with novel resistance-associated BTK mutations in individual patients treated with ibrutinib.

Early Term Delivery and Breastfeeding Outcomes.

OBJECTIVE: Higher rates of adverse outcomes have been reported for early term (37 0 to 38 6 weeks) versus full term (≥ 39 0 weeks) infants, but differences in breastfeeding outcomes have not been systematically evaluated. This study examined breastfeeding initiation and exclusivity in early and full term infants in a large US based sample. METHODS: This secondary analysis included 743 geographically- and racially-diverse women from the Measurement of Maternal Stress Study cohort, and 295 women from a quality assessment at a hospital-based clinic in Evanston, IL. Only subjects delivering ≥ 37 weeks were included. Initiation of breastfeeding (IBF) and exclusive breastfeeding (EBF) were assessed via electronic medical record review after discharge. Associations of IBF and EBF with early and full term delivery were assessed via univariate and multivariate logistic regression. RESULTS: Among 872 women eligible for inclusion, 85.7% IBF and 44.0% EBF. Early term delivery was not associated with any difference in frequency of IBF (p = 0.43), but was associated with significantly lower odds of EBF (unadjusted OR 0.61, 95% CI 0.466, 0.803, p < 0.001). This association remained significant (adjusted OR 0.694, 95% CI 0.515, 0.935, p = 0.016) after adjusting for maternal diabetes, hypertensive disorders of pregnancy, cesarean delivery, maternal age, race/ethnicity, parity, Medicaid status, NICU admission, current smoking, and delivery hospital. CONCLUSIONS FOR PRACTICE: Despite comparable breastfeeding initiation frequencies, early term infants were significantly less likely to be exclusively breastfed compared to full term infants. These data suggest that women with early term infants may benefit from counseling regarding the potential for breastfeeding difficulties as well as additional breastfeeding support after delivery.

Chondrogenic differentiation potential of adult and fetal equine cell types.

OBJECTIVE: To determine the chondrogenic potential of cells derived from interzone tissue, the normal progenitor of articular cartilage during fetal development, compared to that of adult bone marrow-derived and adipose-derived mesenchymal cell isolates. The objective of this study was to compare the chondrogenic potential of fetal musculoskeletal progenitor cells to adult cell types, which are currently used therapeutically to facilitate joint cartilage repair in equine clinical practice. The hypothesis tested was that cells derived from interzone tissue have a chondrogenic potential that exceeds that of adult bone marrow-derived and adipose-derived mesenchymal cell isolates. STUDY DESIGN: In vitro study. ANIMALS: Six young adult horses (15-17 months of age) and 6 equine fetuses aged 45-46 days of gestation. METHODS: Three-dimensional pellet cultures were established under chondrogenic conditions with fresh, primary cells isolated from adult (articular cartilage, bone marrow, adipose, dermis) and fetal (interzone, skeletal anlagen cartilage, dermis) tissues. Cellular morphology, pellet architecture, and proteoglycan synthesis were assessed in the pellet cultures. Steady state levels of ACAN (aggrecan core protein), COL2A1 (collagen type II), and COL1A1 (collagen type I) messenger RNA (mRNA) were compared among these cell types as pellet cultures and monolayer cultures. RESULTS: Adult articular chondrocytes, fetal interzone cells, and fetal anlage cells generated the largest pellets under these chondrogenic culture conditions. Pellets derived from adult articular chondrocytes and fetal anlage cells had the highest scores on a neocartilage grading scale. Fetal anlage and adult articular chondrocyte pellets had low steady-state levels of COL1A mRNA but high COL2A1 expression. Anlage chondrocyte pellets also had the highest expression of ACAN. CONCLUSION: Adult articular chondrocytes, fetal interzone cells, and fetal anlage chondrocytes exhibited the highest chondrogenic potential. In this study, adult adipose-derived cells exhibited very limited chondrogenesis, and bone marrow-derived cells had limited and variable chondrogenic potential. CLINICAL SIGNIFICANCE: Additional investigation of the high chondrogenic potential of fetal interzone cells and anlage chondrocytes to advance cell-based therapies in diarthrodial joints is warranted.

A preliminary investigation of attachment style and inflammation in African-American young adults.

Individuals' social experiences are associated with their mental health, physical health, and even mortality. Over the last 30 years, researchers have examined the ways in which these social experiences might be associated with chronic inflammation - a component underlying many of the chronic diseases of aging. Little research, however, has examined the role of adults' attachment style as a specific social component that might be associated with inflammation. In the present study, we utilized data from a sample of 59 African-American adults from the Maryland Adolescent Development in Context Study (MADICS) to examine the links between attachment avoidance and attachment anxiety and C-reactive protein (CRP) and interleukin (IL)-6. After controlling for demographic characteristics, body mass index, and depressive symptoms, attachment avoidance and anxiety were associated with IL-6 but not CRP. This study adds to the growing body of research identifying the wide range of social experiences associated with inflammation and further suggests that attachment relationship experiences may have implications for biological processes relevant to many chronic diseases of aging.

[Change in paradigm in the treatment of pediatric acquired bone marrow failure syndromes in Hungary]. / Korszakváltás a gyermekkori szerzett csontvelo-elégtelenséggel járó kórképek kezelésében Magyarországon.

INTRODUCTION: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. AIM: To analyse and compare the results of treatment before and after our joining. METHOD: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. RESULTS: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3-393) days, while in severe aplastic anemia median 28 (3-327) days only. Grade II-IV acute graft versus host disease occurred in 22.6%, grade III-IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1-62.5) months. There was a remarkable increase in overall survival comparing the data before (1992-2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. CONCLUSION: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710-1719.

Antenatal depression, psychotropic medication use, and inflammation among pregnant women.

To evaluate the association between psychotropic medication and inflammatory biomarkers in women with antenatal depressive symptoms (ADS). In this cross-sectional secondary analysis of a prospective multicenter observational study, 723 pregnant women underwent a depression screen using the Center for Epidemiologic Studies Depression Scale (CES-D) between 12 and 21 weeks gestation. Self-reported use of medications for depression and/or anxiety was corroborated with the medical record to document exposure to pharmacotherapy. Serum was collected and inflammatory biomarkers (IFNγ, IL13, IL6, IL8, TNFα, CRP) were measured concomitantly. Women were included if they fell into one of three categories: ADS responsive to treatment (CES-D < 16 with medication), ADS not responsive to medication (CES-D ≥ 23 despite medication), and untreated ADS (CES-D ≥ 23 with no medication). Levels of inflammatory biomarkers were compared among groups and multivariable regressions performed. Of the 85 women studied, 16 (19%) had ADS responsive to treatment, 12 (14%) had ADS not responsive to medication, and 57 (67%) had untreated ADS. TNFα concentrations significantly differed (P = 0.016) across the cohorts. Post hoc bivariate analyses demonstrated that women with ADS responsive to treatment had lower serum TNFα than non-responders (p = 0.02) and women with untreated ADS (p = 0.01). There were no differences in IFNγ, IL13, IL6, IL8, or CRP among the groups. Regressions demonstrated that, compared to women with ADS responsive to treatment, non-responders or women with untreated ADS had higher TNFα levels (ß = 0.27, 95% CI 0.02-0.52 and ß = 0.23, 95% CI 0.02-0.44, respectively). Pregnant women on pharmacotherapy who respond to treatment for ADS have lower TNFα compared to women not responsive to medication or women with untreated ADS. These data suggest the possibility that either the therapeutic response in the context of pharmacotherapy is accompanied by modulation of the immune system or that pre-existing higher levels of TNFα may be associated with a poorer response to traditional pharmacotherapy.

Perceptions of parental secure base support in African American adolescents and young adults: A preliminary study of predictive links to adult C-reactive protein.

Within the field of relationship science there is increasing interest in the connections between close relationships and physical health. In the present study, we examined whether adolescents' (~12 years old) and young adults' (~20 years old) perceptions of their parents as a secure base prospectively predict C-reactive protein (CRP), a commonly used marker of inflammatory activity, at age 32 in a well-characterized sample of African Americans. We utilized existing data collected as part of the Maryland Adolescent Development in Context Study (MADICS) to construct measures of perceptions of parental secure base support (SBS), general parental support, and peer support in early adolescence and early adulthood. In the present study, SBS was operationalized as the perceived ability to depend on parents in times of need. Fifty-nine African American MADICS participants who reported on perceived support in early adolescence and early adulthood participated in a follow-up home visit at age 32 during which serum CRP was measured via a blood draw. After controlling for inflammation-related confounds (e.g., tobacco use, body mass index), adolescents' perceptions of parental SBS, but not peer support or general parental support, predicted lower CRP values at age 32 (b = -.92, SE = .34, p < .05). None of the support variables in early adulthood predicted CRP at 32 years. This study adds to a growing literature on relationships and health-related outcomes and provides the first evidence for a link between parental SBS in adolescence and a marker of inflammatory activity in adulthood.

Lipoprotein Lipase as a Prognostic Marker in Chronic Lymphocytic Leukemia.

The marked clinical heterogeneity of CLL makes early prognosis assessment important. Lipoprotein lipase (LPL) has been shown to confer adverse prognosis in CLL, recent data indicating it might also contribute to CLL cell survival and metabolism. We determined LPL mRNA expression in unselected peripheral blood of 84 CLL patients by RT PCR. Results were correlated with other prognostic markers and outcome. 30/84 (40 %) of cases were LPL positive based on the cutoff established by ROC analysis. In LPL positive patients significantly shorter median survival (136 vs 258 months, p < 0.0001) and time to first treatment intervals (36 vs 144 months, p < 0.002) were documented. LPL values correlated with male gender, higher stages, more treatment requirement, CD38 positivity and unmutated IgVH genes. Among cases with 13q deletion, LPL positivity identified a subcohort with poor outcome (median survival 108 months vs NR, p < 0.0001). In multivariate analysis, cytogenetic aberrations and LPL had significant impact on survival. Our results confirm that LPL is a strong predictor of outcome in CLL, able to improve prognostic accuracy in good risk cytogenetic subgroups. The relationship between its prognostic and functional role in CLL needs to be explored further.

Evidence for a Complex Relationship Among Weight Retention, Cortisol and Breastfeeding in Postpartum Women.

Objective To assess the relationship between cortisol slope, a biologic marker of stress, and postpartum weight retention. Methods We included 696 women in a secondary analysis from a multi-site study conducted using principles of community-based participatory research to study multi-level sources of stress on pregnancy outcomes. As a stress marker, we included salivary cortisol slope; the rate of cortisol decline across the day. Pre-pregnancy weight and demographic data were obtained from the medical records. At 6 months postpartum, patients were weighed and returned saliva samples. We built stepwise regression models to assess the effect of demographic variables, cortisol slope and cortisol covariates (wake time, tobacco use and breastfeeding) on postpartum weight retention. Results 45.5 % of participants were African American, 29.2 % White, and 25.3 % Hispanic. Of the Hispanic women 62.5 % were Spanish speaking and 37.5 % were English speaking. In general, participants were young, multiparous, and overweight. Postpartum, almost half (47.6 %) of women studied retained >10 lbs. In multivariable analysis including age, pre-pregnancy BMI and public insurance, cortisol slope was significantly associated with weight retention (ß = -1.90, 95 % CI = 0.22-3.58). However, when the model was adjusted for the cortisol covariates, breastfeeding (ß = -0.63, 95 % CI = -1.01 to -0.24) and public insurance (ß = 0.62, 95 % CI = 0.20-1.04) were the two strongest correlates of weight retention. Conclusions for Practice The association between cortisol slope and postpartum weight retention appears to be influenced breastfeeding status.

Trajectories of relationship stress and inflammatory processes in adolescence.

Researchers have identified cross-sectional links between interpersonal stress and inflammation. Little is known, however, about how these dynamics unfold over time, what underlying immune pathways might exist, or whether moderators such as race could alter the strength of the connection between interpersonal stress and inflammatory processes. We examined whether adolescent girls whose relationship trajectories were characterized by chronic stress would exhibit a proinflammatory phenotype marked by systemic inflammation, heightened cytokine responses to bacterial challenges, and resistance to the anti-inflammatory properties of cortisol. Significant Stress × Race interactions revealed that family stress trajectories predicted glucocorticoid sensitivity and peer stress trajectories predicted cytokine production for White but not Asian girls. Relationship stress trajectories were not associated with systemic inflammation, however. These findings suggest that particular subgroups of adolescent girls who face chronic and elevated stress in their close relationships may be at risk for disruptions to the immune system.

NFKB1 -94ins/delATTG polymorphism is a novel prognostic marker in first line-treated multiple myeloma.

Nuclear factor kappa B (NFKB) plays an important role in multiple myeloma (MM), and bortezomib affects this pathway. We retrospectively analysed the effect of the NFKB1 -94ins/delATTG polymorphism on the survival of 295 MM patients treated at a single centre. The median progression-free survival (PFS) was 790 (659-921) d in patients with NFKB1 homozygous insertion genotype (I/I, n = 99) and 624 (515-733) d in deletion-carriers (I/D&D/D, n = 196, P = 0·013). In multivariate analysis, I/I carriers showed a favourable PFS compared to I/D&D/D with a hazard ratio of 0·622 (0·457-0·847), P = 0·003, in addition to international staging system (ISS) score, fluorescence in situ hybridization (FISH) risk score, age and bortezomib treatment. I/I patients benefited more from bortezomib treatment [PFS 902 (703-1101) and 580 (343-817), P = 0·008] than I/D&D/D patients [PFS 659 (487-831) and 488 (323-653), P = 0·531]; in addition the beneficial effect of low ISS score was not observed in the I/D&D/D group [PFS 639 (454-824) and 650 (458-842), P = 0·226], while it was clear in I/I patients [PFS 1140 (803-1477) and 580 (408-752), P < 0·001]. We conclude that homozygous carriers of the insertion allele of the NFKB1 -94ins/delATTG polymorphism have a better prognosis and probably benefit more from bortezomib treatment than MM patients carrying the deletion allele.

Race/ethnic and socioeconomic differences in stress and immune function in The National Longitudinal Study of Adolescent Health.

Stress and immune function may be important mediators of the strong association between social factors and health over the life course, but previous studies have lacked the data to fully explore these links in a population-based sample. This study utilizes data from Waves I-IV of the U.S. National Longitudinal Study of Adolescent Health (Add Health) to test the associations of race/ethnicity and socioeconomic status (SES) with levels of perceived stress and exposure to stressful life events (SLE) among 11,050 adult respondents aged 24-32 in 2008-2009. We further tested whether race/ethnicity and SES were associated with Epstein-Barr Virus (EBV) specific IgG antibodies, an indirect marker of cell-mediated immune function. Finally, we tested whether measures of stress were associated with EBV IgG and whether there was evidence that they explain any associations between race/ethnicity, SES and EBV IgG. We found strong associations between lower SES and higher levels of perceived stress (OR 2.07, 95% CI 1.73-2.48 for < high school vs. college or above) and a high level of stressful life events (OR 7.47, 95% CI 5.59-9.98 for < high school vs. college or above). Blacks had higher odds of a high level of stressful life events compared to whites (OR 2.00, 95% CI 1.63-2.47), but not higher perceived stress (OR 1.11, 95% CI 0.96-1.28). Blacks also had significantly higher EBV levels compared to whites (ß = 0.136, p < 0.01), but lower SES was not associated with higher EBV IgG. We found no evidence that stressful life events or perceived stress were associated with EBV IgG in this sample, and thus did not account for racial differences in EBV IgG. These results suggest consistent race/ethnic and SES differences in stressful life events, and confirm race/ethnic differences in markers of immune function that may have health implications across the life course.

Medium-sized FLT3 internal tandem duplications confer worse prognosis than short and long duplications in a non-elderly acute myeloid leukemia cohort.

Internal tandem duplications (ITDs) of the fms-like tyrosine kinase 3 (FLT3) gene occur in about 25% of patients with adult acute myeloid leukemia (AML). The aim of our study was to investigate the frequency of FLT3-ITD mutations followed by a detailed analysis of the mutational load and size of ITD insertions in a cohort consisting of 324 patients younger than 60 years old and treated with curative intention. FLT3-ITD alone did not influence overall survival (OS) or disease-free survival (DFS). We observed worse OS and DFS for patients with high mutational load indicative for loss of the FLT3 wild type allele (p = 0.010, p = 0.038, respectively). In multivariate analyses, patients with FLT3-ITD(48-60bp) showed worse OS and DFS compared to other groups (FLT3-ITD(neg), FLT3-ITD (< 48b), FLT3-ITD (> 60bp); p = 0.014, p = 0.019, respectively). Our novel observation suggested that not only high FLT3-ITD load, but also medium-sized ITD insertions (48-60 bp) represented an adverse prognostic subgroup of patients with AML.

Type and location of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia.

Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) are genetic alterations in acute myeloid leukemia (AML). The aim of our study was to investigate the frequency and prognostic effect of IDH1/2 mutations together followed by an individual analysis of each substitution in a Hungarian cohort consisting of 376 patients with AML. IDH1(mut) and IDH2(mut) were mutually exclusive, detected in 8.5% and 7.5% of cases, respectively. IDH1/2(mut) was associated with: older age (p = 0.001), higher average platelet count (p = 0.001), intermediate karyotype (p < 0.0001), NPM1(mut) (p = 0.022) and lower mRNA expression level of ABCG2 gene (p = 0.006). Overall survival (OS), remission and relapse rates were not different in IDH1(mut) or IDH2(mut) vs. IDH(neg). IDH1(mut) and IDH2(mut) were associated differently with NPM1(mut); co-occurrence was observed in 14.3% of IDH1 R132C vs. 70% of R132H carriers (p = 0.02) and in 47.4% of IDH2 R140Q vs. 0% of R172K carriers (p = 0.02). IDH1 R132H negatively influenced OS compared to IDH(neg) (p = 0.02) or R132C (p = 0.019). Particular amino acid changes affecting the same IDH1 codon influence the clinical characteristics and treatment outcome in AML.

Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study.

A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic-Pituitary-Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders. Blood plasma was assayed for cortisol and ACTH every 10 min for 24h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was "personalized" by estimating an individualized set of parameters from each participant's data. Day and nighttime parameters were assessed separately. Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups ("fatigue-predominant" patients with CFS only versus "pain-predominant" patients with FM and comorbid chronic fatigue) from controls (all p's<.05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p's<.05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p<.05). Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol's anti-inflammatory and sleep-modulatory effects. Patients' HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping "behavioral phenotypes" of stress-arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.