Mitogenic properties of a bispecific single-chain Fv-Ig fusion generated from CD2-specific mAb to distinct epitopes [In Process Citation]

The combination of anti-CD2 mAb 9.6 and 9-1, specific for distinct epitopes, induces proliferation of resting human T cells. The mitogenic activity of this mAb mixture depends upon accessory cells and the 9-1 mAb Fc domain. To further study the functional properties of these mAb, their variable regions were cloned and expressed as monospecific single- chain Fv (scFv) proteins fused to the human IgG1 Fc domain (scFvIg). A novel bispecific scFvIg was constructed by cloning the two monospecific scFv binding sites in tandem, with the 9.6 scFv placed N-terminal to the 9-1 scFvIg. Monospecific scFvIg binding to CD2 was comparable to that of the corresponding parental mAb, while the bispecific scFvIg exhibited binding activity similar to that of the 9-1 scFvIg. The combination of 9.6 scFvIg and 9-1 mAb was mitogenic, whereas mixtures including the 9-1 scFvIg were non-stimulatory, confirming the unique properties of the 9-1 IgG3 Fc. Without the IgG3 tail, the bispecific 9.6/9-1 scFvIg was directly mitogenic and was a more potent mitogen than the mAb mixture, but was accessory cell dependent. Unlike the combination of mAb, the bispecific reagent did not directly mobilize calcium in T cells. In comparison to the mAb mixture, bispecific 9.6/9- 1 scFvIg-mediated stimulation of a mixed lymphocyte reaction was significantly more resistant to inhibition of the CD28 co-stimulatory pathway by the inhibitor CTLA-4-Ig. These results show that expression of the 9.6 and 9-1 binding sites together on a bispecific scFvIg increased the mitogenic properties of the mAb and altered the degree of accessory cell signals required for T cell activation.      

维拉帕米增强博莱霉素A5抗癌活性的机制

本文利用流式细胞术(FCM)和动物整体水平的同位素标记药物示踪方法探讨了维拉帕米(VP)增强博莱霉素A₅(BLM)抗癌活性的机制。实验发现VP显著增强BLM对S-180和HEP-2细胞的G₂期阻断效应。VP改变了⁵⁷Co-BLM在荷瘤小鼠部分器官中的分布,增加厂该药在肿瘤中的积聚。VP增強BLM抗癌活性可能是通过增加药物在肿瘤中的积聚,增强药物的G₂期阻断效应以及其它作用实现的。     

A randomized comparison of post-operative pain, quality of life, and physical performance during the first 6 weeks after abdominal or vaginal surgical correction of descensus uteri

AIMS: With respect to urogenital function, vaginal hysterectomy combined with anterior and/or posterior colporraphy has been shown to be superior to abdominal sacrocolpopexy with preservation of the uterus. We performed a randomized trial to compare the effects of both procedures on pain, quality of life and physical performance during the first six weeks after surgery. METHODS: Eighty-two patients were randomized to have surgery either by vaginal or abdominal approach. All patients were asked to complete the RAND-36 before surgery and 6 weeks after surgery and to keep a diary for the first 6 weeks after surgery. This diary assessed the pain perception and use of pain medication, bother of limitations due to the surgery and performance of daily activities after surgery. These outcomes were compared. RESULTS: All patients completed the RAND-36 and 68 patients completed the diary. Patients who had undergone abdominal surgery had a statistically lower score on the health change domain (56 vs 68), bodily pain domain (63 vs 80) and mental health domain (74 vs 81) of the RAND-36, as compared to patients who had undergone vaginal prolapse surgery. During hospital stay, the abdominal group experienced on average more days of pain (4.5 vs 3.0) and impaired mobility (3.7 vs 2.9) as compared to the vaginal group. Patients received more pain medication following abdominal surgery as compared to vaginal surgery. CONCLUSIONS: The vaginal operation to correct a descensus uteri is associated with less pain, better quality of life and better mobility during the first 6 weeks of the recovery period as compared to the abdominal approach.     

A randomised trial comparing low dose vaginal misoprostol and dinoprostone for labour induction

Objective   To compare vaginal misoprostol with dinoprostone for induction of labour.
Design   Randomised multicentre trial.
Setting   Labour wards of one university hospital and two teaching hospitals.
Population   Six hundred and eighty-one women with indication for labour induction at ≥36 weeks of gestation, singleton pregnancy and no previous ceasarean section.
Methods   Misoprostol (25 mcg, hospital-prepared capsule) in the posterior vaginal fornix, every four hours, maximum three times daily or dinoprostone gel (1 mg) every four hours. Oxytocin was administered if necessary.
Main outcome measures   Primary: 'adverse neonatal outcome' (5-minute Apgar score <7 and/or umbilical cord pH <7.15). Secondary: labour duration, mode of delivery and patient satisfaction.
Results   Three hundred and forty-one women received misoprostol and 340 dinoprostone. The median induction–delivery interval was longer in the misoprostol group compared with the dinoprostone group (25 versus 19 hours, P = 0.008). The caesarean section rate was lower in the misoprostol group: 16.1% versus 21%, but this difference was not statistically significant RR = 0.8 (95% CI 0.6–1.04). 'Adverse neonatal outcome' was found to be similar in both groups: 21% in the misoprostol and 23% in the dinoprostone groups. Significantly fewer neonates were admitted to NICU in the misoprostol group compared with dinoprostone 19% versus 26% (RR = 0.7, 95% CI 0.5–0.98).
Conclusions   Misoprostol in this dosing regimen is a safe method of labour induction. NICU admission rates were lower in the misoprostol group. No difference could be detected in patient satisfaction between groups.     

A symptom perception approach to common physical symptoms

This study investigated variables assumed to influence the symptom perception process, as well as the sociodemographic variables of age, gender and socioeconomic status, regarding their relation to common physical symptoms. In addition, it ascertained the predictors of two symptom measurement methods (prospective and retrospective). A group of 152 men and women completed a standardized interview as well as several questionnaires and kept a diary for 4 weeks. Path analyses showed an adequate data fit irrespective of symptom measure. Two main routes to both prospectively and retrospectively measured physical symptoms were found: one from more negative affectivity via a stronger tendency to selective attention and the other from unemployment or a higher number of chronic diseases via a lower quantity of external information. The effect of age on physical symptoms was mediated by the number of chronic diseases and the tendency to selectively attend to bodily sensations. The effects on physical symptoms proved to depend partly on the method of symptom measurement and varied according to the mediating role of negative mood and the tendency to make psychological attributions. Overall, this study highlights the importance of estimating the independent contribution of variables to the experience of common physical symptoms in a comprehensive model while taking into account the method of symptom measurement. In addition, it demonstrates the usefulness of a symptom perception approach for further study.     

Intravenous administration of the conditionally replicative adenovirus Ad5-Δ24RGD induces regression of osteosarcoma lung metastases

Metastatic osteosarcoma (OS) has a very poor prognosis. New treatments are therefore wanted. The conditionally replicative adenovirus Ad5-Δ24RGD has shown promising anti-tumor effects on local cancers, including OS. The purpose of this study was to determine whether intravenous administration of Ad5-Δ24RGD could suppress growth of human OS lung metastases. Mice bearing SaOs-lm7 OS lung metastases were treated with Ad5-Δ24RGD at weeks 1, 2 and 3 or weeks 5, 6 and 7 after tumor cell injection. Virus treatment at weeks 1–3 did not cause a statistically significant effect on lung weight and total body weight. However, the number of macroscopic lung tumor nodules was reduced from a median of >158 in PBS-treated control mice to 58 in Ad5-Δ24RGD-treated mice (p = 0.15). Moreover, mice treated at weeks 5–7 showed a significantly reduced lung weight (decrease of tumor mass, p < 0.05), a significantly increased body weight gain (decrease of disease symptoms, p < 0.005) and a reduced number of macroscopic lung tumor nodules (median 60 versus > 149, p = 0.12) compared to PBS treated control animals. Adenovirus hexon expression was detected in lung tumor nodules at sacrifice three weeks after the last intravenous adenovirus administration, suggesting ongoing viral infection. These findings suggest that systemic administration of Ad5-Δ24RGD might be a promising new treatment strategy for metastatic osteosarcoma.     

Predicting medically unexplained physical symptoms and health care utilization. A symptom-perception approach.

OBJECTIVES: The present study investigated the contribution of demographic characteristics (age, gender, socioeconomic status [SES]) and symptom-perception variables to unexplained physical symptoms and health care utilization. In addition, the consequences of the use of four frequently applied symptom-detection methods for relations among study variables were examined. METHOD: A group of 101 men and women were administered a standardized interview and several questionnaires. Their general practitioners (GPs) rated (un)explained symptoms and consultations over the previous year. RESULTS: Path analyses showed that direct and indirect effects on symptoms and GP consultations depend on method of symptom detection, the largest difference being between self-reported symptoms and registered symptoms. The model including self-reported common symptoms demonstrated the direct and indirect effects of the symptom-perception variables: chronic disease, negative affectivity, selective attention to bodily sensations, and somatic attribution. In the model including registered symptoms, only chronic disease and SES showed effects on symptoms and GP consultations. CONCLUSION: This study demonstrates the usefulness of a symptom-perception approach to the experience of unexplained symptoms, the importance of selection of a symptom-detection method, and the need for different models for the explanation of daily experienced symptoms and their presentation in health care.