Patients with sclerosteosis and disease carriers: Human models of the effect of sclerostin on bone turnover

Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss‐of‐function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino‐terminal propeptide (P1NP), and cross‐linked C‐telopeptide (CTX) in serum of 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age‐ and gender‐matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption. © 2011 American Society for Bone and Mineral Research     

急性淋巴细胞白血病(下)

5 风险评估对病人的复发风险进行评估以确保只有高危病例才被施予极强治疗.研究表明采用成人方案治疗的青少年病人,其效果要显著差于使用儿童方案治疗的同年龄组.     

Evaluation of the mosquitocidal effect of Birbira (Mellitia ferruginea) seed extract against Anopheles arabiensis (Diptera: Culicidae) from Ethiopia

Mosquito control using insecticides has been the most successful intervention known to reduce malaria prevalence and/or incidence. However, over time success has been hampered due to the development of resistance by mosquitoes against chemical insecticides recommended for public health use. Development of effective botanical mosquitocidal compounds however can be potential alternatives tool in malaria vector control. Thus, the present study aimed at investigating the mosquitocidal effect of “Birbira” (Mellitia ferruginea) seed extract against the primary malaria vector, Anopheles arabiensis from Ethiopia. The mosquitocidal activity of M. ferruginea was assessed following WHO susceptibility test procedure. Methanol extract of M. ferruginea seeds was evaluated against third & fourth instar larvae, pupae and, non-blood fed 3–5 days old laboratory strains and field populations of A. arabiensis under laboratory condition. Mortality was then recorded after 24 h exposure. The seed extract of M. ferruginea showed high mosquitocidal activity against larvae, pupae and adult stages of both the laboratory strain and field population of A. arabiensis. The LC₅₀ values for larvae and pupae population from a laboratory strains was, respectively, 14.7 and 41.33 mg/L. While the LC₅₀ values for the larvae and a pupa of the field population were, respectively, 30.88 and 74.54 mg/L. In addition, the LC₉₉ and LD₉₉ values were also identified. The findings of this study indicated that, the extract could be applied on mosquito breeding sites. The plant extract could be also used for indoor residual sprays after conducting the persistency test.     

Granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 greatly enhance the interaction of human eosinophils with opsonized particles by changing the affinity of complement receptor type 3

Eosinophil functions can be modulated by several cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 3 (IL-3), and IL-5. We have investigated the modulatory role of these cytokines on the interaction of human eosinophils with opsonized particles (serum-treated zymosan [STZ]). Addition of STZ to eosinophils isolated from the peripheral blood of normal human donors resulted in an interaction of the STZ particles with only 15% to 25% of the cells. Treatment of the eosinophils with GM-CSF, IL-3, or IL-5 strongly enhanced both the rate of particle binding and the percentage of eosinophils binding STZ. The effect of the cytokines is most likely mediated by a change in affinity of the complement receptor type 3 (CR3) on the eosinophils for the complement fragment iC3b on the STZ particles. This is indicated by the observation that (1) the effect of the cytokines on STZ binding was prevented by a monoclonal antibody against the iC3b-binding site on CR3 and (2) the enhanced binding was already apparent before upregulation of CR3 on the cell surface was observed. In a previous study, similar results were obtained with platelet-activating factor (PAF)-primed eosinophils. Because we found that the cytokines strongly enhanced the STZ-induced PAF synthesis, we investigated the role of both released PAF and cell-associated PAF in the priming phenomenon by the cytokines. Cytokine priming appeared to be largely independent of the synthesis of PAF.     

Amplification of genes encoding human myeloid membrane antigens after DNA-mediated gene transfer

Spontaneous amplification of genes encoding two different human myeloid surface antigens was observed after DNA-mediated gene transfer of cellular DNA from the human myeloid cell line HL-60 into NIH-3T3 mouse fibroblasts. Transformed recipient cells with highly amplified expression of either of two donor membrane polypeptides, gp150 or p67, were isolated with a fluorescence-activated cell sorter (FACS), using monoclonal antibodies specific for human myeloid cells. Immunoprecipitation of enzymatically radioiodinated polypeptides from the surface of transformed NIH-3T3 cells confirmed that expression of these proteins was amplified tenfold to 20-fold in comparison to their expression on human myeloid cell lines. The cellular DNA of cloned secondary and tertiary transformants expressing high levels of gp150 and p67 contained amplified sets of DNA restriction fragments that hybridized with human repetitive DNA sequences. Cytogenetic analysis of subclones overexpressing gp150 revealed extrachromosomal double minutes (DMs), whose presence correlated with the unstable expression of the membrane polypeptide. Human sequences in gp150-positive clones did not localize to chromosomes, consistent with their association with extrachromosomal DMs. By contrast, p67-positive subclones stably expressed the antigen, and in situ hybridization to metaphase spreads demonstrated that amplified human DNA sequences were integrated into a specific marker chromosome. Cytogenetic analysis of the parental NIH- 3T3 subclone used in these studies disclosed DMs in a low percentage of metaphases, suggesting that the recipient cells have a propensity for amplifying donor DNA.     

阿司匹林与结直肠癌存活率的关系

背景及目的：随机对照临床试验已经表明阿司匹林可降低结直肠癌的发生风险,动物实验还发现其可抑制肿瘤生长与转移,但阿司匹林与已确诊结直肠癌患者存活率的关系仍不可知.本研究探讨了在已确诊的结直肠癌患者中,阿司匹林与结直肠癌总体存活率的关系.     

Human Calcitonin Delivery in Rats by Iontophoresis

Abstract— In-vitro iontophoresis (0·33 mA cm⁻²) of calcitonin (50 μg mL⁻¹, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.