Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy.

A high tricuspid regurgitant jet velocity (TRV) signifies a risk for or established pulmonary hypertension (PH), which is a serious complication in thalassemia patients. The underlying pathophysiology in thalassemia subgroups and potential biomarkers for early detection and monitoring are not well defined, in particular as they relate to spleen removal. To better understand some of these unresolved aspects, we examined 76 thalassemia patients (35 non-transfused), 25 splenectomized non-thalassemia patients (15 with hereditary spherocytosis), and 12 healthy controls. An elevated TRV (>2.5 m/s) was found in 25/76 (33 %) of the patients, confined to non-transfused or those with a late start of transfusions, including patients with hemoglobin H-constant spring, a finding not previously described. These non or late-transfused patients (76 % splenectomized) had significantly increased platelet activation (sCD40L), high platelet count, endothelial activation (endothelin-1), and hemolysis (LDH, plasma-free Hb), while hypercoagulable and inflammatory markers were not significantly increased. The same markers were increased in the seven patients with confirmed PH on cardiac catheterization, suggesting their possible role for screening patients at risk for PH. A combination of hemolysis and absence of spleen is necessary for developing a high TRV, as neither chronic hemolysis in the non-splenectomized thalassemia patients nor splenectomy without hemolysis, in the non-thalassemia patients, resulted in an increase in TRV.

Increased leucocyte apoptosis in transfused ß-thalassaemia patients.

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from ß-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3/7, 48% higher caspase-8 and 88% higher caspase-9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl-2 (BCL2), (-27·3%/year), and caspase-9 activity (-13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.

Nutritional Deficiencies Are Common in Patients with Transfusion-Dependent Thalassemia and Associated with Iron Overload.

Patients with thalassemia are frequently deficient in key micronutrients. Attempts to correct these inadequacies through nutritional supplementation have been met with some success, although disparities between intake and circulating levels continue to be observed. This study employed a convenience sample of 41 well-nourished transfusion dependent patients with thalassemia to identify possible mechanisms behind nutritional deficiencies. Each subject completed a Block 2005© Food Frequency Questionnaire (FFQ), through which macro and micronutrient intake was quantified. Fasting blood was drawn to assess vitamins A, C, D, E, copper, selenium, zinc and hematologic parameters. Dietary intake was found to be inadequate compared to Institute of Medicine (IOM) recommendations for many of the fat-soluble vitamins, as well as calcium and zinc. Circulating deficiencies of vitamins C, D, copper, zinc and γ tocopherol were also present in over 20% of patients. Many individuals who consumed an adequate dietary intake had deficient levels of circulating nutrients, which suggest alternative etiologies of nutrient excretion or loss, in addition to higher micronutrient requirements. Liver iron concentration displayed a significant negative relationship with vitamins C (r=-0.62, p<0.001), E (r=-0.37, p=0.03), and zinc (r=-0.35, p=0.037), indicating that in iron-overloaded patients, these nutrients are either endogenously consumed at higher rates or sequestered within the liver, resulting in a functional nutrient deficiency. While this study identified hepatic iron overload to be a significant cause of nutritional deficits commonly observed in patients with thalassemia, multiple etiologies are simultaneously responsible. In response to these findings, nutritional status should be monitored regularly in at-risk patients with thalassemia, and prophylactically addressed with supplementation or aggressive chelation to avoid associated co-morbidities.

Qualitative and/or quantitative drinking water recommendations for pediatric obesity treatment.

OBJECTIVE: The qualitative recommendation to 'drink water instead of caloric beverages' may facilitate pediatric obesity treatment by lowering total energy intake. The quantitative recommendation to 'drink enough water to dilute urine' might further facilitate weight loss by increasing fat oxidation via cell hydration-mediated changes in insulin. METHODS: This 8 week randomized intervention tested whether both qualitative-plus-quantitative (QQ) drinking water recommendations result in more weight loss than the qualitative recommendation alone (Q) in 25 children (9-12y) with body mass index at or above the 85th Percentile, given a reduced glycemic diet and usual physical activity. Random urine osmolality, saliva insulin, and body weight were assessed weekly. Mixed models explored if insulin mediated an effect of urine osmolality on weight loss. RESULTS: In intention-to-treat analyses, QQ and Q participants did not differ significantly with respect to level of urine osmolality, saliva insulin, or weight loss. Only 4 out of 16 QQ participants complied with instruction to drink enough water to dilute urine, however. In completers analyses, the compliant QQ participants, who diluted urine osmolality from 910 ± 161 mmol/kg at baseline to below 500 mmol/kg over time (8 week mean±SE: 450 ± 67 mmol/kg), had significantly lower saliva insulin over time (8 week mean±SE: 13 ± 8 pmol/l vs. 22 ± 4 pmol/l) and greater weight loss (mean ± SE: -3.3 ± 0.7kg vs. -2.0 ± 0.5 kg) than compliant Q participants (7 out of 9 participants) who maintained elevated urine osmolality over time (8- week mean±SE: 888 ± 41 mmol/kg). Urine osmolality below 500 mmol/kg was significantly associated with weight loss. Change in saliva insulin partially explained the association. CONCLUSIONS: QQ recommendations may increase weight loss for those able to dilute urine. Work is warranted to pursue cell hydration effects of drinking water for pediatric obesity treatment.

RBC deformability and amino acid concentrations after hypo-osmotic challenge may reflect chronic cell hydration status in healthy young men.

Biomarkers of chronic cell hydration status are needed to determine whether chronic hyperosmotic stress increases chronic disease risk in population-representative samples. In vitro, cells adapt to chronic hyperosmotic stress by upregulating protein breakdown to counter the osmotic gradient with higher intracellular amino acid concentrations. If cells are subsequently exposed to hypo-osmotic conditions, the adaptation results in excess cell swelling and/or efflux of free amino acids. This study explored whether increased red blood cell (RBC) swelling and/or plasma or urine amino acid concentrations after hypo-osmotic challenge might be informative about relative chronic hyperosmotic stress in free-living men. Five healthy men (20-25 years) with baseline total water intake below 2 L/day participated in an 8-week clinical study: four 2-week periods in a U-shaped A-B-C-A design. Intake of drinking water was increased by +0.8 ± 0.3 L/day in period 2, and +1.5 ± 0.3 L/day in period 3, and returned to baseline intake (0.4 ± 0.2 L/day) in period 4. Each week, fasting blood and urine were collected after a 750 mL bolus of drinking water, following overnight water restriction. The periods of higher water intake were associated with significant decreases in RBC deformability (index of cell swelling), plasma histidine, urine arginine, and urine glutamic acid. After 4 weeks of higher water intake, four out of five participants had ½ maximal RBC deformability below 400 mmol/kg; plasma histidine below 100 µmol/L; and/or undetectable urine arginine and urine glutamic acid concentrations. Work is warranted to pursue RBC deformability and amino acid concentrations after hypo-osmotic challenge as possible biomarkers of chronic cell hydration.

Orange juice limits postprandial fat oxidation after breakfast in normal-weight adolescents and adults.

Caloric beverages may promote weight gain by simultaneously increasing total energy intake and limiting fat oxidation. During moderate intensity exercise, caloric beverage intake depresses fat oxidation by 25% or more. This randomized crossover study describes the impact of having a caloric beverage with a typical meal on fat oxidation under resting conditions. On 2 separate days, healthy normal-weight adolescents (n = 7) and adults (n = 10) consumed the same breakfast with either orange juice or drinking water and sat at rest for 3 h after breakfast. The meal paired with orange juice was 882 kJ (210 kcal) higher than the meal paired with drinking water. Both meals contained the same amount of fat (12 g). For both age groups, both meals resulted in a net positive energy balance 150 min after breakfast. Resting fat oxidation 150 min after breakfast was significantly lower after breakfast with orange juice, however. The results suggest that, independent of a state of energy excess, when individuals have a caloric beverage instead of drinking water with a meal, they are less likely to oxidize the amount of fat consumed in the meal before their next meal.

Fertility potential in thalassemia major women: current findings and future diagnostic tools.

Preserving fertility, preventing early menopause, and predicting reproductive ability have become crucial for many adult thalassemia major females. Luteinizing hormone/follicle-stimulating hormone (LH/FSH) and estradiol, commonly used for assessment of fertility potential in thalassemia, have a poor predictive value. Current reproductive practice uses markers of ovarian reserve testing, which were not yet studied in thalassemia women. We explored the relationship between liver iron concentration (LIC) and fertility status in 26 females (mean 30 years old). Seventeen (65%) of them experienced primary or secondary amenorrhea. Levels of LH/FSH and estradiol were low or undetectable in 48% and 35% of patients, respectively and did not correlate with age, presence of amenorrhea, and LIC. This further addresses the need for utilization of current available methods for assessment of fertility capacity in thalassemia, which will also allow future correlation with pituitary iron measures by MRI as well as early intervention for fertility preservation.