In vivo molecular targeted radiotherapy

Unsealed radionuclides have been in clinical therapeutic use for well over half a century. Following the early inappropriate clinical administrations of radium salts in the early 20th century, the first real clinical benefits became evident with the use of (131)I-sodium iodide for the treatment of hypothyroidism and differentiated thyroid carcinoma and (32)P-sodium phosphate for the treatment of polycythaemia vera. In recent years the use of bone seeking agents (89)Sr, (153)Sm and (186)Re for the palliation of bone pain have become widespread and considerable progress has been evident with the use of (131)I-MIBG and (90)Y-somatostatin receptor binding agents. Although the use of monoclonal antibody based therapeutic products has been slow to evolve, the start of the 21st century has witnessed the first licensed therapeutic antibody conjugates based on (90)Y and (131)I for the treatment of non-Hodgkin's lymphoma. The future clinical utility of this form of therapy will depend upon the development of radiopharmaceutical conjugates capable of selective binding to molecular targets. The availability of some therapeutic radionuclides such as (188)Re produced from the tungsten generator system which can produce activity as required over many months, may make this type of therapy more widely available in some remote and developing countries.Future products will involve cytotoxic radionuclides with appropriate potency, but with physical characteristics that will enable the administration of therapeutic doses with the minimal need for patient isolation. Further developments are likely to involve molecular constructs such as aptamers arising from new developments in biotechnology.Patient trials are still underway and are now examining new methods of administration, dose fractionation and the clinical introduction of alpha emitting radiopharmaceutical conjugates. This review outlines the history, development and future potential of these forms of therapy.     

Antibody fragments selected by phage display against the nuclear localization signal of the HIV-1 Vpr protein inhibit nuclear import in permeabilized and intact cultured cells

The HIV-1 Vpr protein harbors a nuclear localization signal in its N-terminal domain. A peptide bearing this domain and which is designated VprN has been used as a target to screen a phage display single chain Fv (scFv) library. Here we report the isolation of anti-VprN scFv fragments from this library. The purified scFv fragments were able to bind the VprN peptide in an ELISA-based system and to inhibit VprN-mediated nuclear import in permeabilized as well as in intact microinjected cells. Furthermore, the anti-VprN scFv fragments recognized the full-length recombinant Vpr protein and inhibited its nuclear import. The same scFv fragments did not inhibit nuclear import mediated by the nuclear localization signal of the SV40 large T-antigen demonstrating a specific effect. The use of the described inhibitory anti-VprN scFv fragments to study nuclear import of viral karyophilic proteins and their therapeutic potential is discussed.     

Silent period to transcranial magnetic stimulation: construction and properties of stimulus–response curves in healthy volunteers

Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus–response (S–R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900–1800 mg). The S–R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R²=0.947–0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V₅₀ (the SI at which SP duration is halfway between Min and Max) were 230.8±3.31 ms (x±SEM), –11.51±3.31 ms, 11.56±0.65%, and 49.82±0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V₅₀ (51.69±0.72 vs 47.95±0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3±5.8% at baseline to 59.4±10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6±42.4 ms to 143.5±46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V₅₀ and SP threshold (from 54.5±4.9% to 59.9±7.2% and from 29.1±6.4% to 34.6±6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S–R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.Presented in part at the meeting of the EFNS, Helsinki, September 2003     

Magnetic resonance imaging of femoral head development in roentgenographically normal patients

Magnetic resonance images (MRI) of 22 patients with roentgenographically normal hips were reviewed retrospectively and the findings categorized according to age. With increasing maturity, the MR intensity of the femoral heads on spin echo images increased, as marrow fat became a dominant tissue in the head. The femoral head pattern was relatively inhomogeneous, with a broad band of diminished intensity extending in a posteromedial to anterolateral direction, corresponding to the pattern of trabecular bone. The femoral capital epiphyses were visible in younger patients as structures of bright intensity which remained evident through early adulthood. The articular cartilage of the hip joint was noted as a distinctive halo around the femoral head. An understanding of the MR pattern of the normal hip will aid in the early recognition of pathologic conditions, such as osteonecrosis.     

Remote metabolic effects of cerebrovascular lesions: magnetic resonance and positron tomography imaging

Summary Combined Positron Emission Tomography (PET) and Proton Magnetic Resonance Imaging (MRI) study were performed in six patients with chronic supratentorial stroke to investigate whether remote hypometabolic regions revealed by PET showed any abnormality on MRI. Either regional oxygen consumption (n=4) or glucose utilization (n=2) were measured using PET and the ¹⁵O steady state ¹⁸FGD technique, respectively. Four patients, with deeply located brain lesions, showed a significant metabolic reduction in the overlying cerebral cortex. In the remaining two patients, affected by a large cortical infarct, there was a significant crossed cerebellar hypometabolism. The MRI weighted by the parameters spin density (), spin lattice (T₁) and spin-spin (T₂) relaxation times were obtained employing various sequences in the same subjects. In no patient did the MRI show any contrast modification in these hypometabolic remote regions, suggesting that subtle loss of tissue and/or biochemical change do not underlie the reduction in metabolic rate.     

The Effects of Magnetic Resonance Imaging on Implantable Pulse Generators

The effects of magnetic resonance imaging were assessed on four dual chamber and two single chamber pulse generators. The tests were performed with a resistive, water-cooled magnet operating at 0.15 T. The 6.4-MHz radiofrequency (RF) field was operated at a maximum power of 1,000 watts with a period adjusted from 130 to 500 ms. Reed switch closure occurred in all six pulse generators tested when placed near the entrance of the magnetic resonance imaging scanner, and the generators reverted to asynchronous operation unless programmed to the "magnet off" mode. None of the pulse generators exhibited any alterations in programmed parameters or in the ability to be reprogrammed after RF pulsing. When the RF field was turned on, there was no change in the asynchronous paced cycle length in four pulse generators; however, during RF scanning there was rapid cardiac stimulation at the RF pulse period in one single chamber and one dual chamber pulse generator.     

Tumor nuclear grade,estrogen receptor,and progesterone receptor: Their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer

Summary Previous reports by us have shown that the outcome of breast cancer patients who have received systemic adjuvant therapy is influenced by tumor estrogen or progesterone receptor (ER or PR) content or by nuclear grade. This publication provides information regarding the relative merit of those three markers. Findings from patients receiving L-PAM plus 5-FU (PF) or PF plus tamoxifen (PFT) indicate that the disease-free survival and survival within each regimen was almost identical when related to either ER, PR, or nuclear grade. Those having tumors with either of the receptors 10 fmol or a good nuclear grade had a better outcome through five postoperative years than did those with ER or PR 0–9 fmol or poor nuclear grade. The magnitude of the difference was similar for each of the three discriminants. Since they were found to be of equal predictive value, one marker might well serve as a substitute for another. Cox regression analyses, however, clearly indicate that ER, PR, and nuclear grade have an independent influence on outcome and that a more accurate assessment of outcome is obtained when more than one marker is employed. Thus, information should be obtained on as many markers as possible. This conclusion is supported by observations presented which indicate that nuclear grade in combination with either or both of the receptors is a better predictor than either marker alone and that, as indicated by life table probability values and relative odds ratios, an increasing number of favorable tumor prognostic indicators results in a better patient outcome particularly in PFT-treated patients. A possible explanation is considered for why the separation of receptor/nuclear grade categories is more orderly and pronounced in PF-treated patients receiving tamoxifen than in those given PF alone. See Appendix I     

亚急性联合变性的临床分析

目的探讨亚急性联合变性(SCD)的临床特点、发病机制及电生理和磁共振成像的诊断价值.方法对14例SCD患者的临床资料进行回顾性分析.结果发现所有SCD患者发病均由维生素B12缺乏所引起.肢体感觉异常,深感觉减退,共济失调及痉挛性轻瘫是SCD常见的症状和体征.该病早期易误诊,电生理检查有极高的敏感性,磁共振成像可以确定脱髓鞘的部位.结论血清维生素B12浓度测定,体感诱发电位及磁共振对诊断和治疗有重要作用.