Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling. (Blood. 2005;105:410-419)      

Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function

Rat models of hypertension, eg, spontaneously hypertensive stroke-prone rats (SHRSP), display reduced angiotensin-converting enzyme 2 (ACE2) mRNA and protein expression compared with control animals. The aim of this study was to investigate the role of ACE2 in the pathogenesis of hypertension in these models. Therefore, we generated transgenic rats on a SHRSP genetic background expressing the human ACE2 in vascular smooth muscle cells by the use of the SM22 promoter, called SHRSP-ACE2. In these transgenic rats vascular smooth muscle expression of human ACE2 was confirmed by RNase protection, real-time RT-PCR, and ACE2 activity assays. Transgene expression leads to significantly increased circulating levels of angiotensin-(1-7), a prominent product of ACE2. Mean arterial blood pressure was reduced in SHRSP-ACE2 compared to SHRSP rats, and the vasoconstrictive response to intraarterial administration of angiotensin II was attenuated. The latter effect was abolished by previous administration of an ACE2 inhibitor. To evaluate the endothelial function in vivo, endothelium-dependent and endothelium-independent agents such as acetylcholine and sodium nitroprusside, respectively, were applied to the descending thoracic aorta and blood pressure was monitored. Endothelial function turned out to be significantly improved in SHRSP-ACE2 rats compared to SHRSP. These data demonstrate that vascular ACE2 overexpression in SHRSP reduces hypertension probably by locally degrading angiotensin II and improving endothelial function. Thus, activation of the ACE2/angiotensin-(1-7) axis may be a novel therapeutic strategy in hypertension.     

A novel anti-CD146 monoclonal antibody,AA98, inhibits angiogenesis and tumor growth

The goal of our study was to raise monoclonal antibodies (mAbs) against endothelial cell-surface proteins specific for tumor vasculature. Here, we describe the generation and intensive characterization of mAb AA98, including its functional properties and its antigen identification. In our study, an enhanced mAb AA98 immunoreactivity was observed on stimulated human umbilical vein endothelial cells (HUVECs). In addition, mAb AA98 showed remarkably restricted immunoreactivity against intratumoral neovasculature compared with blood vessels of normal tissues. We identified the AA98 antigen as human CD146, an adhesion molecule belonging to the immunoglobulin superfamily. Data from in vitro experiments imply structural and signaling functions for endothelial CD146; however, the role of CD146 in vivo is largely unknown. Here, we show that mAb AA98 displays antiangiogenic properties in vitro and in vivo. Proliferation and migration of HUVECs were inhibited by mAb AA98 as was angiogenesis in chicken chorioallantoic membrane (CAM) assays and tumor growth in 3 xenografted human tumor models in mice. Our data provide new insights into the function of CD146 on endothelial cells, validate CD146 as a novel target for antiangiogenic agents, and demonstrate that mAb AA98 has potential as a diagnostic and therapeutic agent in vascular and cancer biology.     

Influence of chitosan coating on the oral bioavailability of gold nanoparticles in rats

Gold nanoparticles are one of the most extensively investigated metallic nanoparticles for several applications. It is less toxic than other metallic nanolattices. The exceptional electrical and thermal conductivity of gold make it possible to be administered as non-invasive radiofrequency irradiation therapy that produces sufficient heat to kill tumor cells. Nanoparticles are generally administered intravenously instead of orally due to negligible oral absorption and cellular uptake. This study evaluated the oral bioavailability of gold nanoparticles coated with chitosan (C-AuNPs), a natural mucoadhesive polymer. We employed traditional method of evaluating bioavailability that involve estimation of maximum concentrations and area under the curve of 3?nm chitosan coated gold nanoparticles (C-AuNPs) in the rat plasma following intravenous and oral administrations (0.8?mg and 8?mg/kg body weight respectively). The oral bioavailability of C-AuNPs was found to be 2.46% (approximately 25 folds higher than polyethylene glycol (PEG) coated gold nanoparticles, reported earlier). These findings suggest that chitosan coating could be better than PEG coating for the enhancement of oral bioavailability of nanoparticles.     

FIP Perspectives: Realising global patient safety goals requires an integrated approach with pharmacy at the core

Patient safety is becoming increasingly recognised as a top priority for action that requires a collective and coordinated response. The leading cause of harm or injury in health care systems is medication errors. As medicines experts, the pharmacy workforce plays a key role in minimising medication errors and mitigating the global challenge of patient safety. Pharmacists’ involvement in ensuring patient safety is crucial. Pharmacists are charged with the responsibility to ensure that when a patient receives and uses a medicine, it will not cause harm or death. The International Pharmaceutical Federation (FIP) recognises the critical role the pharmacy plays in realising global, regional and national patient safety goals; and works with its partners, stakeholders and members around the world to advocate for the role of pharmacy in achieving this global patient safety agenda and to envision a world of safe access to medicines and care.     

Effect of SAMe-TT2R2 score and genetic polymorphism on the quality of anticoagulation control in Qatari patients treated with warfarin

Journal of Thrombosis and Thrombolysis - There is no strong evidence on pharmacogenetics role on the quality of INR control after the initiation phase and on the maintenance of stable INR on the...     

Oestradiol‐Induced Synapse Formation in the Female Hippocampus: Roles of Oestrogen Receptor Subtypes

During the oestrus cycle, varying spine synapse density correlates positively with varying local synthesis of oestradiol in the hippocampus. In this context, the roles of the oestrogen receptor (ER) subtypes ERα and β are not fully understood. In the present study, we used neonatal hippocampal slice cultures from female rats because these cultures synthesise oestradiol and express both receptor subtypes, and inhibition of oestradiol synthesis in these cultures results in spine synapse loss. Using electron microscopy, we tested the effects on spine synapse density in response to agonists of both ERα and ERβ. Application of agonists to the cultures had no effect. After inhibition of oestradiol synthesis, however, agonists of ERα induced spine synapse formation, whereas ERβ agonists led to a reduction in spine synapse density in the CA1 region of these cultures. Consistently, up‐regulation of ERβ in the hippocampus of adult female aromatase‐deficient mice is paralleled by hippocampus‐specific spine synapse loss in this mutant. Finally, we found an increase in spine synapses in the adult female ERβ knockout mouse, but no effect in the adult female ERα knockout mouse. Our data suggest antagonistic roles of ERβ and ERα in spine synapse formation in the female hippocampus, which may contribute to oestrus cyclicity of spine synapse density in the hippocampus.     

The effect of timing of maternal tetanus,diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels – A prospective study

Background

The Centers for Disease Control and Prevention recommend Tdap immunization during pregnancy, preferably at 27–36 weeks.

Aim

To ascertain whether there is a preferential period of maternal Tdap immunization during pregnancy that provides the highest concentration of pertussis-specific antibodies to the newborn.

Methods

This prospective study measured pertussis-specific antibodies in paired maternal-cord sera of women immunized with Tdap after the 20th week of their pregnancy (n = 61).

Results

The geometric mean concentrations (GMCs) of Immunoglobulin G (IgG) to pertussis toxin (PT) were higher in the newborns’ cord sera when women were immunized at 27–30⁺⁶ weeks (n = 21) compared with 31–36 weeks (n = 30) and >36 weeks (n = 7), 46.04 international units/milliliter (IU/mL) (95% CI, 24.29–87.30) vs. 8.69 IU/mL (95% CI, 3.66–20.63) and 21.12 IU/mL (95% CI, 7.93–56.22), p < 0.02, respectively. The umbilical cord GMCs of IgG to filamentous hemagglutinin (FHA) were higher in the newborns’ cord sera when women were immunized at 27–30⁺⁶ weeks compared with 31–36 weeks and >36 weeks, 225.86 IU/mL (95% CI, 182.34–279.76) vs. 178.31 IU/mL (95% CI, 134.59–237.03) and 138.03 IU/mL (95% CI, 97.61–195.16), p < 0.02, respectively.

Conclusions

Immunization of pregnant women with Tdap between 27–30⁺⁶ weeks was associated with the highest umbilical cord GMCs of IgG to PT and FHA compared with immunization beyond 31 weeks gestation. Further research should be conducted to reaffirm these finding in order to promote an optimal pertussis controlling policy.