N-cadherin in osteolineage cells is not required for maintenance of hematopoietic stem cells

There is evidence suggesting that N-cadherin expression on osteoblast lineage cells regulates hematopoietic stem cell (HSC) function and quiescence. To test this hypothesis, we conditionally deleted N-cadherin (Cdh2) in osteoblasts using Cdh2(flox/flox) Osx-Cre mice. N-cadherin expression was efficiently ablated in osteoblast lineage cells as assessed by mRNA expression and immunostaining of bone sections. Basal hematopoiesis is normal in these mice. In particular, HSC number, cell cycle status, long-term repopulating activity, and self-renewal capacity were normal. Moreover, engraftment of wild-type cells into N-cadherin-deleted recipients was normal. Finally, these mice responded normally to G-CSF, a stimulus that mobilizes HSCs by inducing alterations to the stromal micro-environment. In conclusion, N-cadherin expression in osteoblast lineage cells is dispensable for HSC maintenance in mice.     

Pancreatic iron and glucose dysregulation in thalassemia major

Pancreatic iron overload and diabetes mellitus (DM) are common in thalassemia major patients. However, the relationship between iron stores and glucose disturbances is not well defined. We used a frequently sampled oral glucose tolerance test (OGTT), coupled with mathematical modeling, and magnetic resonance imaging (MRI) to examine the impact of pancreatic, cardiac, and hepatic iron overload on glucose regulation in 59 patients with thalassemia major. According to OGTT results, 11 patients had DM, 12 had impaired glucose tolerance (IGT), 8 had isolated impaired fasting glucose (IFG), and 28 patients had normal glucose tolerance (NGT). Patients with DM had significantly impaired insulin sensitivity and insulin release. Insulin resistance was most strongly associated with markers of inflammation and somatic iron overload, while disposition index (DI) (a measure of beta cell function) was most strongly correlated with pancreas R2*. Patients with DM and IGT had significantly worse DI than those with NGT or IFG, suggesting significant beta cell toxicity. One‐third of patients having elevated pancreas R2* had normal glucose regulation (preclinical iron burden), but these patients were younger and had lower hepatic iron burdens. Our study indicates that pancreatic iron is the strongest predictor of beta cell toxicity, but total body iron burden, age, and body habitus also influence glucose regulation. We also demonstrate that MRI and fasting glucose/insulin are complementary screening tools, reducing the need for oral glucose tolerance testing, and identify high‐risk patients before irreversible pancreatic damage. Am. J. Hematol., 2011. © 2011 Wiley Periodicals, Inc.     

Pituitary iron and volume predict hypogonadism in transfusional iron overload

Hypogonadism is the most common morbidity in patients with transfusion‐dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan‐Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < ?2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r² of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate‐to‐severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy. Am. J. Hematol. 2011. © 2011 Wiley Periodicals, Inc.     

Fractionated doses of gemtuzumab ozogamicin with escalated doses of daunorubicin and cytarabine as first acute myeloid leukemia salvage in patients aged 50-70-year old: a phase 1/2 study of the acute leukemia French association

This Phase 1/2 study aimed to determine optimal doses of daunorubicin (DNR; mg/m²) and cytarabine (mg/m²) to be combined with fractionated doses of gemtuzumab ozogamicin (GO, Mylotarg®; 3 mg/m² on day 1, 4, and 7) satisfying safety requirements. Three dose levels of DNR/AraC were investigated namely (45, 100), (60, 100), and (60, 200). Patients included were acute myeloid leukemia in first relapse, aged 50–70 years. Hematological recovery was 31 days for neutrophil and 32 days for platelet counts. A documented infectious episode > Grade 2 occurred in 11/20 patients (55%). None of the 20 patients had signs of veno‐occlusive disease. Overall, eleven patients reached complete remission (CR), two CR with incomplete platelets recovery. The results showed that combination of fractionated GO doses with DNR at 60 mg/m²/d for 3 days and cytarabine at 200 mg/m²/d for 7 days is tolerable and could be further investigated in the front‐line therapy. Am. J. Hematol., 2012. © 2011 Wiley Periodicals, Inc.     

Marked attenuation of shock burden by the use of antitachycardia pacing therapy in a patient with an implanted cardioverter-defibrillator

A 76-year-old man was admitted to our institution for elective exchange of his implanted cardioverter-defibrillator generator. Nine years earlier, he had been diagnosed with nonischemic cardiomyopathy and nonsustainable ventricular tachycardia. At that time, he had received a single-chamber implanted cardioverter-defibrillator, which was upgraded to a dual-chamber implanted cardioverter-defibrillator 3 years later. In the course of the current admission, routine device interrogation during exchange of the patient's implanted cardioverter-defibrillator generator revealed 150 episodes of ventricular tachycardia in the preceding 7 months, 137 of which had been successfully treated by antitachycardia pacing therapy without shock. These findings show the remarkable effectiveness of antitachycar-dia pacing in terminating ventricular tachycardia while preventing the delivery of shocks, minimizing patient discomfort, and avoiding implanted cardioverter-defibrillator battery depletion.     

The Impact of Preload Alteration on the Myocardial Performance Index through Implementing Positive End Expiratory Pressure

Load independent methods should be used for the assessment of ventricular function. Debate still exists regarding whether tissue Doppler imaging (TDI) indices are influenced by preload. Here, we evaluated the effect of positive end expiratory pressure (PEEP) related preload reduction on both conventional pulsed Doppler (PD) and TDI myocardial performance index (MPI). Thirty-eight mechanically ventilated patients of 3 months to 12 years old (mean ± SD age of 30 ± 11months) without overt heart disease were enrolled. Doppler mitral inflow velocities, isovolumetric contraction and relaxation times and aortic ejection time in addition to TDI peak systolic, early and late diastolic velocities from the basal segment of left ventricular lateral wall were determined for each patient before and after applying high PEEP (10 cmH(2) O).PD-MPI was load dependent (0.61 ± 0.22 vs. 0.78 ± 0.25, P = 0.002). However, TDI-MPI did not significantly change after the use of high PEEP declining the left ventricular volume loading (0.78 ± 0.21 vs. 0.84 ± 0.22, P = 0.23). Hence, regarding various interfering pathophysiologic factors particularly preload reduction, it seems that TDI-MPI would be a more reliable index for the assessment of ventricular function.     

The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [CuII(NKB)2] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells

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Effect of Weight Reduction Following Bariatric Surgery on Serum Visfatin and Adiponectin Levels in Morbidly Obese Subjects

ObjectiveAdipokines are signaling and mediator proteins secreted from adipose tissue. A novel adipokine, visfatin, was reported as a protein which was mainly expressed in visceral adipose tissue. Controversial results have been shown regarding the changes of adipokines following weight reduction. So we investigated the effects of weight reduction on serum concentrations of adiponectin and visfatin in morbidly obese subjects.Methods35 severely obese patients (26 females and 9 males), aged 15-58 years, were studied. Anthropometric parameters and biochemical parameters as well as adiponectin and visfatin were analyzed before and 6 weeks after weight reduction.ResultsAnthropometric indices decreased significantly. Blood levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride were reduced significantly. The reduction of visfatin and the elevation of adiponectin were significant as well. However, other parameters like fasting glucose and insulin did not change. Moreover, we could not find any significant correlation between the change of serum visfatin and that of adiponectin. Conclusions: 6-week weight reduction after bariatric surgery resulted in decreased serum visfatin and increased adiponectin levels. However, we cannot find any significant correlation between changes of adiponectin, visfatin, BMI, waist circumference, and insulin resistance. Further studies with different design are suggested to clarify these associations.Key Words: Adiponectin, Visfatin, Morbid obesity, Bariatric surgery, Weight loss