A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

用19个生化基因位点研究普通级Z:ZCLA长爪沙鼠的遗传多样性

实验动物资源是国家生命科学研究的重要科技资源。实验动物资源的共享和充分利用是生物科技创新的基础和保障。有效的共享机制和合理的共享方式是实现实验动物资源共享和充分利用的重要保障,是规范实验动物资源共享行为和确保共享安全的迫切需要。     

Randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants with ventilator-dependent chronic lung disease

This randomized controlled trial was designed to answer the question: does administration of dexamethasone to neonates with bronchopulmonary dysplasia decrease the need for assisted ventilation? Twenty-five infants with a birth weight < 1501 g, requiring mechanical ventilation and FiO₂ of ± 0.30 at 21-35 days of age, were randomized to treatment with iv dexamethasone or to sham injections for 12 days. The primary outcome criterion was extubation within seven days after study entry. Treatment (n= 12) and control (n= 13) groups were well matched at entry. Dexamethasone facilitated weaning from assisted ventilation (p= 0.0154). There was no increased incidence of infection. Dexamethasone treatment resulted in a significant increase in glucosuria (p= 0.0002) and in systolic blood pressure (p= 0.0034). There was a significant decrease in heart rate (p= 0.0001) and a significant weight loss (p= 0.0002) following dexamethasone treatment. Dexamethasone treatment facilitated weaning from assisted ventilation but several systemic effects were noted that deserve further evaluation before dexamethasone becomes routine treatment.     

Effects of positive and negative pressure ventilation on cerebral blood volume of newborn infants

The effects of intermittent positive airway and continuous negative extrathoracic pressure ventilation on cerebral blood volume in preterm infants were studied using near infrared spectroscopy. In 12 infants continuous negative extrathoracic pressure caused a median decrease in cerebral blood volume of 0.14ml/100ml brain (95% confidence intervals (CI) 0.035–0.280) compared with no respiratory support. Oxygenated and deoxygenated haemoglobin also decreased, implying increased venous drainage as the main effect. In 17 infants intermittent positive pressure ventilation also caused a median reduction in cerebral blood volume of 0.06 ml/100 ml brain (95% CI 0.010–0.115) compared with endotracheal positive airway pressure. Deoxygenated haemoglobin increased by 0.07 ml/100 ml brain (95% CI 0.010–0.100) while oxygenated haemoglobin decreased by O.lOml/lOOml brain (95% CI 0.005–0.175). The increase in deoxygenated haemoglobin implies decreased venous drainage and the decrease in oxygenated haemoglobin implies that other factors may also be significant. Heart rate, blood pressure and oxygen saturation were monitored continuously and remained stable.     

Immunohistochemical analysis of the stage-specific expression of Ia antigens in the rat mammary gland during pregnancy and lactation

The expression of Class II MHC antigens in the rat mammary gland was assessed by immunoperoxidase using monoclonal antibodies against rat homologues of the murine I-A and I-E antigens. Our results showed that, while I-A and I-E were inconspicuous in undifferentiated mammary epithelium in virgin rats, during early pregnancy, the ductal epithelium becomes intensely positive for both antigens. A monoclonal antibody specific for macrophages showed that they were abundant in the stroma but did not correspond to the epithelial staining. During late pregnancy and lactation, the ductal epithelium expressed varying levels of Ia, while the alveolar epithelial cells were consistently Ia-negative. Ia-positive mononuclear cells of round or dendritic morphology present in the alveolar areas were enumerated as cells per high power field (HPF). Maximal cell counts for I-A and I-E were seen in late pregnancy and early lactation, with a significant decline in mid-lactation. Counts were higher in intraepithelial locations than in the subjacent connective tissue at all stages. The possible role of these stage-specific alterations in regulating local immune responses and transfer of immune components into milk is discussed.     

Retrospective study of the management of chemotherapeutic extravasation injury

Despite the now widespread experience with the administration of chemotherapeutic agents in oncology, extravasation injuries still occur. Furthermore, the most appropriate management of such injuries is not known. The authors examined the current treatment options for extravasation injury and the incidence of this problem. All cases of extravasation referred to the plastic surgery service at one institution from 1994 through 1996 were examined. During a 6-year period there were 44 cases of extravasation injury identified in 42 patients. Comparison with a previous study conducted 15 years before at the same institution revealed a significant reduction in the incidence of extravasation injuries during that time (0.01% vs. 0.1%; = 0.00). The site of extravasation was peripheral in 32 cases and central in 12. Paclitaxel and doxorubicin were the two most common drugs involved. The local infusion of antidotes was not performed routinely. Only 26 of the 42 patients were referred to the plastic surgery service for care. Only 10 of those 26 patients required local ulcer excision and closure to achieve a healed wound. The mean time between injury and referral was 40 days. This time did not predict the subsequent need for a surgical procedure. Most patients, including the remaining 16 referred to the plastic surgery service, did not require surgical intervention. All were watched expectantly, and their injuries healed spontaneously. In conclusion, the incidence of extravasation is decreasing, most likely as a result of the diligence in the administration and identification of extravasation injuries as well as the result of the use of more central infusion sites. Most cases can be managed conservatively, with directed surgical treatment of the ulceration when appropriate.     

Interactions of cyclosporines with lipid membranes as studied by solid-state nuclear magnetic resonance spectroscopy and high-sensitivity titration calorimetry

Cyclosporin A (CyA) interacts with lipid membranes. Binding reaction and membrane location of CyA and analogs were examined with 2H-NMR, high-sensitivity isothermal titration calorimetry (ITC), and CD spectroscopy. Effects of CyA and charged analogs on the phosphocholine head group and on the membrane interior were investigated using selectively deuterated phospholipids. Incorporation of cyclosporin generated small disordering of the lipid acyl chains. Binding of CyA and neutral and positively charged analogs to lipid membranes showed endothermic heats of reaction between + 5.9 and + 11.3 kcal/mol, whereas enthalpy of binding was close to zero for the negatively charged derivative. Binding constants of cyclosporines to liposomal membranes were in the range of K(P) = 1650-5560 M(- 1) depending on the cholesterol content. (2)H-NMR provides evidence that CyA is essentially located in the interior of the bilayer membrane. For the charged analogs an additional interaction occurs at the head group level, placing the polar groups of these CyA analogs in the vicinity of the phosphocholine dipoles. The association of CyA and its analogs is accompanied by a positive enthalpy change, which is overcompensated by positive entropy changes. Binding of CyA to lipid membranes thus follows the classical hydrophobic effect, which is in contrast to many other peptide-lipid binding reactions.     

Determinants of physician unwillingness to offer medical abortion using mifepristone.

PURPOSE: We sought to identify factors associated with contemplating versus not contemplating offering medical abortion with mifepristone among physicians not opposed to it. METHODS: We analyzed data from a Kaiser Family Foundation survey of a nationally representative sample of 790 American obstetrician/gynecologists and primary care physicians. Our study sample consisted of 419 physicians who were not personally opposed to medical abortion and could be classified as not actively considering (precontemplation) or actively considering (contemplation) offering mifepristone. We conducted multivariate logistic regression to predict being unlikely to offer mifepristone (i.e., in the precontemplation stage of change). PRINCIPAL FINDINGS: In 2001, 1 year after U.S. Food and Drug Administration (FDA) approval, 5% of physicians surveyed were offering mifepristone. Among the 750 physicians not offering mifepristone, 57% were not opposed. Of those not opposed, 74% reported that they were unlikely to offer mifepristone in the next year (precontemplation) as compared to 23% who might offer it (contemplation). Independent predictors of being in the precontemplation stage were being a primary care versus OB/GYN physician (odds ratio [OR] 3.29, p = .02), being in private versus hospital-based practice (OR 2.40, p = .03), and lacking concerns about FDA regulations (OR 2.06, p = .01) or violence and protests (OR 1.93, p = .03) as barriers to offering mifepristone. CONCLUSIONS: For precontemplation-stage physicians, the most efficient strategy for increasing the availability of medical abortion may be to design programs that emphasize clinical benefits and feasibility to stimulate interest in the procedure. For contemplation-stage physicians, the optimum approach may be one that helps to overcome barriers associated with FDA regulations and concerns about violence and protests.     

Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study

BACKGROUND AND PURPOSE: The time courses of total creatine (Cr), N-acetylaspartate (NAA), choline (Cho), and myo-inositol have not previously been investigated in the follow-up of contrast-enhancing multiple sclerosis (MS) plaques. Therefore, over a period of 2 years, we compared the absolute concentrations of these metabolites between patients treated with a placebo or 15 +/- deoxyspergualin (DSG) and between clinical groups with relapsing-remitting or secondary-progressive MS. METHODS: Sixteen patients, recruited from a pharmacological study of DSG, and 11 healthy control subjects were investigated by a stimulated-echo acquisition mode sequence (TR/TE = 3000/20). The selected volume initially contained a contrast-enhancing plaque, which was followed up for a period of 2 years. RESULTS: In contrast-enhancing plaques, Cho was significantly elevated and showed a significant reduction after both 3 and 12 months. The initially normal Cr significantly increased between 3 and 12 months, and was negatively correlated with plaque volume on T1-weighted MR images. NAA initially showed normal values, a significant decrease at 1 month, and a slow recovery over 2 years. Myo-inositol did not show a clear tendency. The placebo group did not differ from the treated group, nor did the relapsing-remitting group differ from the secondary-progressive group. CONCLUSION: The contradictory time courses of Cr and NAA show that an absolute quantification in proton MR spectroscopy in MS is necessary to avoid a false interpretation of reduced NAA/Cr ratios. The increase in Cr is probably due to remyelination. The initial dip and later recovery of NAA seem to be related to diminishing edema and remyelination.     

血清SOD、MDA、NO与突发性聋的相关研究

目的：通过对突发性聋病人血中一氧化氮（NO）、丙二醛（MDA）、超氧化物歧化酶（SOD）含量的检洲，探讨突聋与血氧自由基和自由基的清除剂SOD之间的关系。方法：采用硝酸还原酶法测定了30例突聋病人血中NO含量，并以25例同期体检正常的健康人为对照组；同时还用硫代巴比妥酸比色法测定MDA含量，用黄嘌呤氧化酶法测定SOD含量。砖呆；应用金纳多、能量合剂、克林臭（即马来酸桂哌齐特，钙通道阻滞药）联合静脉输入，突聋各组的听力均有不同程度提高，有效率在78．57％以上。治疗后同对照组相比，血清NO、MDA水平明显低于患病之初，而SOD活性明显高于治疗之前，P〈0．01。结论；检测突聋病人血中N0、MDA、SOD的含量，能帮助我们探讨突聋的发病机理，估计预后。血氧自由基的升高可能是突聋发病因素之一，而SOD的含量可以帮助我们估计预后。