Perturbations in the erythroid marrow progenitor cell pools may play a role in the augmentation of HbF by 5-azacytidine

In vivo observations on the kinetics of F cells and of fetal hemoglobin (HbF) synthesis and in vitro studies of erythroid progenitors, their number, and the gamma-gene expression in their progeny were carried out in baboons (Papio cynocephalus) treated with 5-azacytidine. Maximum effect on the increase of HbF production in vivo was observed only when an expanded erythroid marrow population was present. In these animals, as well as in normal animals, treatment resulted in a significant reduction of the late erythroid progenitor cell pools (erythroid clusters and erythroid colony-forming units, CFU-E) in the marrow. This reduction was more pronounced among those progenitors grown in the absence of added erythropoietin, and it was followed by a rebound a few days after treatment cessation, reflecting the accumulation of regenerating progenitors. An early increase in the in vitro synthesis of HbF in erythroid clusters and CFU-E colonies was observed. This increase was further documented at the cellular level, with immunofluorescent labeling of colonies with monoclonal anti-gamma- globin chain antibodies. In contrast to the findings in late progenitors, the number of erythroid burst-forming unit (BFU-E) colonies and the synthesis of HbF in these colonies was not influenced significantly by 5-azacytidine treatment. It is proposed that the toxic effects of 5-azacytidine on late progenitors, leading to faster mobilization of earlier progenitors to the next more mature compartment, play a role in the in vivo augmentation of HbF synthesis by this drug. This perturbation in the progenitor cell population kinetics and the presumed hypomethylation of the surviving differentiating cells may act synergistically to produce a maximum HbF response after 5-azacytidine treatment.     

Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors

A novel hematopoietic growth factor for primitive hematopoietic progenitor cells, the ligand for the flt3/flk2 receptor, (FL), has been recently purified and its gene has been cloned. In the present study, we investigated the effects of FL on the proliferation and differentiation of normal and leukemic myeloid progenitor cells. We demonstrate that FL is a potent stimulator of the in vitro growth of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 3 (IL-3), or G-CSF-dependent granulocyte-macrophage committed precursors from Lin- CD34+ bone marrow cells of normal donors. By contrast, FL does not affect the growth of erythroid-committed progenitors even in the presence of erythropoietin. The effect of FL on the proliferation and on the in vitro growth of clonogenic leukemic precursor cells was studied in 54 acute myeloid leukemia (AML) cases. Fresh leukemia blasts from 36 of 45 patients with AML significantly responded to FL without any relation to the French-American-British (FAB) subtype. FL stimulated the proliferation of leukemic blasts in a dose-dependent fashion. Synergistic activities were seen when FL was combined with G-CSF, GM-CSF, IL-3, or stem cell factor (SCF). FL as a single factor induced or increased significantly colony formation by clonogenic precursor cells from 21 of 24 patients with AML. In the presence of suboptimal and optimal concentrations of G-CSF, GM-CSF, IL3, SCF, or a combination of all factors, FL strongly enhanced the number of leukemic colonies (up to 18-fold). We also evaluated the induction of tyrosine phosphorylated protein on FL stimulation in fresh AML cells. We demonstrate that, on FL stimulation, a band of phosphorylated protein(s) of about 90 kD can be detected in FL- responsive, but not in FL-unresponsive cases. This study suggests that FL may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor with other cytokines.     

EFI region 8 Balkan external proficiency testing for HLA typing: Results of 15 years

Istanbul Medical Faculty, Department of Medical Biology, as the first EFI‐accredited HLA laboratory in Turkey since 1999 has been organizing both national and international quality control tests for HLA typing under the banner of the “Balkan external proficiency testing (BEPT)” encompassing countries from EFI regions 8. The first round of BEPT in 2004 was organized for low‐resolution HLA‐A,‐B typing by molecular methods and 12 centres participated in the exercise. In 2005, low‐resolution HLA‐DR typing was added, and in 2007, low‐resolution HLA‐C and DQ typing were added to the exercise and 28 centres participated. In 2015, high‐resolution (four digits or higher typing) HLA‐A,‐B,‐C,‐DR and –DQ typing added to the exercise and 40 centres participated. In the last 2 years, 2017 and 2018, the number of participating centres increased to 48 and 52, respectively. When the distribution of low‐resolution typing methods applied in the exercises were investigated, it was found that 82% of the centres in the first round of BEPT in 2004 used PCR‐SSP, whereas in the last round in 2018, 26% of the centres preferred SSP, while the rest used SSO (50%) or SSP and SSO (24%) methods. Methods for high‐resolution typing were SBT (41%), NGS (18%), SSO (18%), SSP (6%), SBT + NGS (6%) and SBT + SSP (11%). In 15th trial for BEPT, nomenclature mistake rate was 12%, and erroneous result rate was 6% for HLA samples. The most common mistakes in the exercises were nomenclature mistakes. The EFI Standards Version 7.0 is stated "HLA type can be reported using a hyphen if homozygosity is not proven by family studies." In order to provide standard results among HLA laboratories and since accurate HLA typing leads to significant increase of graft and patient survival, quality control exercises should be performed in all HLA‐based tests periodically.     

经皮椎体注入骨水泥治疗老年脊椎骨质疏松压缩性骨折

目的:观察经皮椎体内注入骨水泥(聚甲基丙烯酸甲酯)治疗脊椎骨质疏松压缩性骨折的疗效。方法:自2005-06/2006-06吉林大学中日联谊医院骨科及大庆龙南医院骨科对35例40个椎体的骨质疏松压缩性骨折患者使用经皮椎体内注射骨水泥,行椎体成形术。成形材料:美国KYPHON公司生产的骨水泥,生产准许号:(GB/T19001-2000和YY/T0287-1996)。结果:35例患者均参加随访6个月。术后均未出现骨水泥外漏、脊髓或马尾神经损伤等并发症。35例患者中5例出现穿刺部位局部疼痛,服用镇痛药物后均缓解。疼痛完全消失25例,占71.4%;明显缓解8例,占22.6%;轻度缓解2例,占6.0%;无缓解0例。15例患者在术后72h内均能下床活动。术后未再发生压缩性骨折及疼痛。结论:经皮椎体注入骨水泥可以有效改善椎体骨质疏松压缩性骨折患者疼痛症状,随访6个月未出现充填剂不良性宿主反应,临床疗效较好。     

The evaluation of perceived sources of stress and stress levels among Turkish dental students

Objective : The purpose of this study was to identify sources of stress and to evaluate stress levels among Turkish dental students and also to investigate the role of year of study and gender on perceived stressors. Methods : This study included 308 dental students. Dental Environment Stress (DES) questionnaire, Beck Depression Inventory (BDI) and Spielberger State Trait Anxiety Inventory (STAI) were used to collect data. Also, some factors considered to be effective on stress levels of dental students were questioned. Data were statistically analysed with Kruskal Wallis and Mann Whitney U tests. Results : The most stress provoking factors were fear of failing the year, completion of clinical requirements and amount of assigned work. Statistically significant differences were found between years of study and gender for many stressors. There was statistically significant difference between years of study and gender for mean DES scores but no statistically significant differences were found between years of study for mean BDI, STAI scores. There was statistically significant difference between genders for STAI‐1. Choice rank of dental school has affected stress levels of dental students. Conclusion : This study showed that perceived sources of stress of clinical students were very similar and stress levels of these students were lower than preclinical students, also gender was effective on stressors and stress levels.     

Is phenytoin contraindicated in patients receiving cranial irradiation ?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.     

Intestinal permeability in the newborn

Passive intestinal permeability in 33 newborn babies was studied using feeds containing lactulose and mannitol. Each marker is thought to pass across the gut wall by a different route; lactulose by a paracellular and mannitol by a transcellular pathway. Neither is metabolised and both are wholly and solely excreted by the kidney; urinary recovery is a measure of the intestinal uptake. Babies born before 34 weeks' gestation exhibited a higher intestinal permeability to lactulose than more mature babies, and all preterm babies showed an appreciable decline in lactulose absorption during the first week of oral feeds. Babies of 34 to 37 weeks' gestation achieved a 'mature' intestinal permeability to lactulose within four days of starting oral feeds. These findings may reflect the immaturity of the gut of the preterm baby rather than a process essential to adaptation to enteral nutrition.     

Transient renal tubular acidosis in pregnancy

Renal tubular acidosis in pregnancy is a very rare disorder. Most cases are either inherited or secondary to maternal disease or ingestion of toxic chemicals. We report a 22-year-old woman, previously healthy, who presented at 27 weeks of gestation with preterm labor. Investigation revealed renal tubular acidosis with no obvious etiology. Labor was stopped with various tocolytic drugs and her electrolyte imbalance was corrected. She was delivered at 36 weeks, by cesarean for a nonreassuring fetal heart tracing, of an appropriate-for-gestational-age infant weighing 2905 g. Evaluation 3 and 6 months postpartum revealed gradual, but complete resolution of the acidosis and electrolyte abnormality. The infant is now 7 months old, is growing normally with normal electrolytes, and with no evidence of acidosis.