CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin

Background

CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.

Design and Methods

We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined.

Results

As assessed by flow cytometry, stem cell-enriched CD34⁺/CD38⁻/CD123⁺ leukemic cells expressed significantly higher levels of CD33 compared to normal CD34⁺/CD38⁻ stem cells. Moreover, highly enriched leukemic CD34⁺/CD38⁻ cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34⁺/CD38⁻ cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells.

Conclusions

CD33 is expressed abundantly on immature CD34⁺/CD38⁻ stem cells and may serve as a stem cell target in chronic myeloid leukemia.     

Emotion differentiation in autism spectrum disorder

Autism spectrum disorder (ASD) is commonly associated with reduced ability to recognize emotions in others. It is less clear however, whether ASD is also associated with impaired knowledge of one's own emotions. In the current study we present a first examination of how much knowledge individuals with ASD have about their emotions by investigating their ability to differentiate between emotions. Across two lab tasks that measured to what extent and how people differentiate between their own feeling states and semantic emotion terms, results showed that ASD individuals differentiated less than typically developing individuals. Yet, both groups of participants similarly categorized emotions according to previously established theoretical categories. These findings indicate that while both give similar meaning to emotions, individuals with ASD make less subtle distinctions between emotions. With low levels of emotion differentiation being linked to reduced well-being, these findings may help to better understand the high prevalence of internalizing problems associated with ASD.     

CD34 marks angiogenic tip cells in human vascular endothelial cell cultures

The functional shift of quiescent endothelial cells into tip cells that migrate and stalk cells that proliferate is a key event during sprouting angiogenesis. We previously showed that the sialomucin CD34 is expressed in a small subset of cultured endothelial cells and that these cells extend filopodia: a hallmark of tip cells in vivo. In the present study, we characterized endothelial cells expressing CD34 in endothelial monolayers in vitro. We found that CD34-positive human umbilical vein endothelial cells show low proliferation activity and increased mRNA expression of all known tip cell markers, as compared to CD34-negative cells. Genome-wide mRNA profiling analysis of CD34-positive endothelial cells demonstrated enrichment for biological functions related to angiogenesis and migration, whereas CD34-negative cells were enriched for functions related to proliferation. In addition, we found an increase or decrease of CD34-positive cells in vitro upon exposure to stimuli that enhance or limit the number of tip cells in vivo, respectively. Our findings suggest cells with virtually all known properties of tip cells are present in vascular endothelial cell cultures and that they can be isolated based on expression of CD34. This novel strategy may open alternative avenues for future studies of molecular processes and functions in tip cells in angiogenesis.     

Diagnosis, Clinical Presentation, and In-Hospital Mortality of Severe Malaria in HIV-Coinfected Children and Adults in Mozambique

Background.?Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria. Methods.?HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status. Results.?HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P?相似文献   

Impact of Early Parenteral Nutrition on Metabolism and Kidney Injury

A poor nutritional state and a caloric deficit associate with increased morbidity and mortality, but a recent multicenter, randomized controlled trial found that early parenteral nutrition to supplement insufficient enteral nutrition increases morbidity in the intensive care unit, including prolonging the duration of renal replacement therapy, compared with withholding parenteral nutrition for 1 week. Whether early versus late parenteral nutrition impacts the incidence and recovery of AKI is unknown. Here, we report a prespecified analysis from this trial, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study. The timing of parenteral nutrition did not affect the incidence of AKI, but early initiation seemed to slow renal recovery in patients with stage 2 AKI. Early parenteral nutrition did not affect the time course of creatinine and creatinine clearance but did increase plasma urea, urea/creatinine ratio, and nitrogen excretion beginning on the first day of amino acid infusion. In the group that received late parenteral nutrition, infusing amino acids after the first week also increased ureagenesis. During the first 2 weeks, ureagenesis resulted in net waste of 63% of the extra nitrogen intake from early parenteral nutrition. In conclusion, early parenteral nutrition does not seem to impact AKI incidence, although it may delay recovery in patients with stage 2 AKI. Substantial catabolism of the extra amino acids, which leads to higher levels of plasma urea, might explain the prolonged duration of renal replacement therapy observed with early parenteral nutrition.The development of AKI is a frequent and devastating condition in patients admitted to the intensive care unit (ICU). Short-term mortality is high and increases with worsening AKI stages.¹ In AKI survivors, renal recovery is often incomplete, progression to ESRD may be accelerated, and longer-term mortality rates are increased compared with non-AKI patients.^2,3 Patient management consists of maximal prevention of additional renal damage by hemodynamic stabilization and prevention of (iatrogenic) nephrotoxicity. A curative strategy for established AKI is currently unavailable.⁴Observational studies, finding associations between a poor nutritional state and increased morbidity and mortality of AKI patients⁵ and between accumulation of a caloric deficit and poor renal and survival outcome of ICU patients,^6,7 have led to the hypothesis that feeding could ameliorate kidney injury and improve survival of ICU patients. However, nutrition, especially parenteral nutrition (PN), also has potential complications.^8–11 Because of the lack of adequately designed studies, nutritional guidelines are largely based on expert opinion.^12–14 These opinions invariably recommend the early initiation of enteral feeding but substantially differ in their recommendation on when to start supplemental PN.The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study was the first large, multicenter, randomized controlled trial (RCT) addressing this important question. The study showed that early initiation of PN increased dependency on intensive care compared with withholding supplemental PN for 1 week (hereafter labeled early PN and late PN, respectively).¹⁵ Indeed, early PN prolonged the ICU and hospital length of stay (LOS), increased the incidence of new infections, and prolonged the need for mechanical ventilation. Renal harm was suggested by a clear prolongation of the duration of renal replacement therapy (RRT) in ICU and a trend for more AKI (defined as a doubling or more of ICU admission plasma creatinine). However, the number of patients requiring RRT was unaltered, and recovery to premorbid kidney function was not investigated.It was preplanned to study the detailed impact of early versus late PN on the incidence and recovery of AKI and the time course of blood/urine markers of renal function during ICU stay.¹⁶ A priori, we hypothesized that early PN would attenuate kidney injury. However, the original study findings suggested that AKI incidence and renal recovery could be aggravated by increased macronutrient provision in the acute phase of critical illness.     

Ulnar shortening osteotomy for ulnar ideopathic impaction syndrome

Twenty-eight patients were treated by ulnar shortening osteotomy for static or dynamic ulnar impaction syndrome. Ulnar variance was measured on a true anteroposterior radiograph. There were 25 wrists that were too long, two neutral, and one that was short. Bones were shortened by a mean of 3.5 mm. Mean follow-up time was 29 months (range 7–60), all with confirmed consolidation. At final follow-up mean grip strength had improved from 67% to 75%, mean Disabilities of the Arm, Shoulder, and Hand (DASH) score from 40 (range 12–83) to 26 (range 0–61) and mean range of movement from 80% (range 40%–100%) to 88% (range 50%–100%). Smoking, age at operation, type of osteotomy (transverse or oblique), dominance of hand, and sex did not influence consolidation or functionality. Special attention was paid to the anatomy of the distal radioulnar joint and the inclination of the sigmoid notch of the radius. There was no correlation between the anatomy and the functional outcome scores. Mean consolidation time (10 months) (range 2–32) and return to work were longer than in similar studies. Our findings confirm the usefulness of ulnar shortening osteotomy in the relief of ulnocarpal impingement symptoms.     

Reflections of Caretakers on the Process of Implementation of Life Space Crisis Intervention at a Therapeutic Centre for Youngsters with Emotional and Behavioural Disorders

Life space crisis intervention (LSCI) is a therapeutic and verbal strategy used to intervene when children are in crisis. It has its roots in the work of Aichorn, Redl, Wineman and Bettelheim, and is part of the milieu-therapeutic tradition. In 2000, LSCI was introduced at the Orthopedagogical Observation and Treatment Centre, a school and day unit for 60 children with emotional and behavioural disorders affiliated with the Department of Orthopedagogy at Ghent University (Belgium). The particular position of orientation towards ‘therapeutic environments’ in the department’s history has encouraged the integration of LSCI in the daily activities of the departments’ school (Broekaert et al., Int J Ther Communities 30(2):122–145, 2009). In 2003, LSCI was implemented and studied in several Flemish Institutes. Positive effects were found on school results, attendance in the classroom and number of conflicts. In this article, the reflections of the caretakers are taken into account. Analyses of these reflections resulted in 4 major themes: content of job and tasks, the youth in the centre, working with the youth in the centre, and cooperation with colleagues and other teams. The results of this analysis will be discussed.