High proportion of anergic B cells in the bone marrow defined phenotypically by CD21(-/low)/CD38- expression predicts poor survival in diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is the commonest lymphoma that is highly aggressive where one-third of the patients relapse despite effective treatment. Interaction between the lymphoma cells and the non-clonal immune cells within the bone marrow microenvironment is thought to play a critical role in the pathogenesis of DLBCL. METHODS: We used flow cytometry to characterize the proportion of B cell subpopulations in the bone marrow (N = 47) and peripheral blood (N = 54) of 75 DLBCL patients at diagnosis and study their impact on survival. RESULTS: Anergic B cells in the bone marrow (BM), characterized as having CD21(-/low)/CD38- expression, influenced survival with high numbers (defined as > 13.9%) being associated with significantly shorter overall survival (59.7 months vs 113.6 months, p = 0.0038). Interestingly, low numbers of anergic B cells in the BM (defined as ≤13.9%) was associated with germinal center B cell type of DLBCL (p = 0.0354) that is known to have superior rates of survival when compared to activated B cell type. Finally, Cox regression analysis in our cohort of patients established that the inferior prognosis of having high numbers of anergic B cells in the bone marrow was independent of the established Revised International Prognostic Index (R-IPI) score. CONCLUSIONS: High proportion of anergic B cells in the BM characterized by CD21(-/low)/CD38- expression predicts poor survival outcomes in DLBCL.

Glucose production in response to glucagon is comparable in preterm AGA and SGA infants.

BACKGROUND AND AIMS: Low plasma glucose concentrations are more often detected in small-for-gestational-age (SGA) than in appropriate-for-gestational-age (AGA) infants. This is ascribed to impaired glucose production due to presumed lower liver glycogen stores in SGA infants. The change in glucose production induced by glucagon is considered to be an indicator of liver glycogen content. We compared the effect of glucagon on glucose kinetics in preterm AGA and SGA infants. METHODS: In 5 AGA and 5 SGA preterm infants (postnatal age: 3-6 days) glucose production and gluconeogenesis were measured using stable isotopes immediately before and for 1 h after a bolus of glucagon. RESULTS: After glucagon the plasma glucose concentration and glucose production increased significantly over time (P<0.05 and P<0.0001, respectively). The changes were comparable between AGA and SGA infants. Glycogenolysis contributed 75-80% to the increase in glucose production. CONCLUSION: The increase in glucose production after glucagon was similar in preterm AGA and SGA infants, and mainly due to an increase in glycogenolysis. Based on the assumption that glycogenolysis is an indicator of liver glycogen content, our data do not support the hypothesis that liver glycogen content is lower in preterm SGA compared to AGA infants after the first postnatal day.

Alanine administration does not stimulate gluconeogenesis in preterm infants.

Gluconeogenesis partially depends on sufficient precursor supply, and plasma alanine concentrations are generally low in preterm infants. Stimulation of gluconeogenesis may contribute to the prevention of hypoglycemia, an important clinical problem in these infants. In this study we evaluated the effect of extra precursor supply on gluconeogenesis in preterm infants. In 11 infants, gestational age < or = 32 weeks, glucose production rate (GPR) and gluconeogenesis were measured using the [6,6-(2)H(2)]glucose dilution technique and mass isotopomer distribution analysis with [2-(13)C]glycerol, respectively. Unlabeled glucose was administered throughout the study period at a rate of 22 micromol. kg(-1). min(-1). Five infants received alanine (1.5 mg. kg(-1). min(-1)) during the last 3 hours of the study protocol, and 6 infants served as controls. In the control group the rate of gluconeogenesis and GPR remained constant at 4.0 +/- 0.3 micromol. kg(-1). min(-1) and 8.3 +/- 0.6 micromol. kg(-1). min(-1), respectively. In the alanine group plasma alanine concentrations increased from 45 +/- 23 to 829 +/- 115 micromol/L (P =.001); gluconeogenesis and GPR did not differ from control: 3.8 +/- 0.2 micromol. kg(-1). min(-1) and 6.4 +/- 2.0 micromol. kg(-1). min(-1), respectively. We conclude that administration of the gluconeogenic precursor alanine does not stimulate gluconeogenesis in preterm infants, despite a sharp increase in plasma alanine concentrations. We speculate either a restricted capacity of the enzymes involved in the gluconeogenic pathway or a low secretion rate of glucoregulatory hormones as causative mechanisms involved in the gluconeogenic pathway in the preterm neonate.

Adaptation of glucose production and gluconeogenesis to diminishing glucose infusion in preterm infants at varying gestational ages.

In preterm infants low plasma glucose concentrations are frequently observed. We hypothesized that the infants' ability to adapt endogenous glucose production to diminishing exogenous supply is disturbed, but will improve with increasing gestational age. Glucose production rate and gluconeogenesis were measured using stable isotope techniques with [6,6-2H2]glucose and [2-13C]glycerol in 19 preterm infants (10 < or = 30 wk and nine >30 wk gestational age) on d 5.0 +/- 1.4 of life. Exogenous glucose was administered at a rate of 33 micromol x kg-1 x min-1 followed by 22 micromol x kg-1 x min-1. In the first 2 h after the decrease in exogenous supply, plasma glucose concentration declined comparably in both groups: < or =30 wk, from 4.3 +/- 1.2 to 3.2 +/- 0.9 mM; >30 wk, from 3.7 +/- 0.7 to 3.0 +/- 0.6 mM. Thereafter, only in infants >30 wk an increase was observed, to 3.4 +/- 0.8 mM. Glucose production rate increased comparably in both groups: < or =30 wk, from 6.0 +/- 4.1 to 8.8 +/- 3.4 micromol x kg-1 x min-1; >30 wk, from 7.8 +/- 4.6 to 11.6 +/- 5.2 micromol x kg-1 x min-1. This increase was equivalent to approximately 30% of the decline in exogenous glucose. Gluconeogenesis increased comparably in both groups: <30 wk, from 3.2 +/- 1.2 to 4.5 +/- 1.3 micromol x kg-1 x min-1; >30 wk, from 4.3 +/- 1.9 to 6.8 +/- 2.9 micromol x kg-1 x min-1. We conclude that preterm infants can only partly compensate a decline in exogenous glucose supply by increasing endogenous glucose production rate, probably because of limitations in the final common pathway of intracellular glucose metabolism (i.e. glucose-6-phosphatase). The ability to maintain the plasma glucose concentration after a decrease in exogenous supply is better preserved in infants >30 wk owing to more efficient adaptation of peripheral glucose utilization.