ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND KININ METABOLISM: EVIDENCE THAT ACE INHIBITORS MAY INHIBIT A KININASE OTHER THAN ACE

1. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, and also metabolizes bradykinin-(1–9) to bradykinin-(1–7) and bradykinin-(1–7) to bradykinin-(1–5). Increases in endogenous kinin levels may contribute to the therapeutic effects of ACE inhibitors. 2. ACE inhibitors increase vascular levels of both bradykinin-(1–9) and its ACE cleavage product bradykinin-(1–7), at doses below the threshold for ACE inhibition, leading to the proposal that ACE inhibitors may also inhibit a non-ACE kininase which cleaves both kinin peptides; this non-ACE kininase may be the major pathway of kinin metabolism in the vasculature and some other tissues. 3. In support of this proposal, ACE inhibitors potentiate bradykinin-(1–9) effects at doses which have little or no effect on ACE activity, as indicated by angiotensin I conversion to angiotensin II. ACE inhibitors also potentiate the actions of ACE-resistant kinin analogues, which may be susceptible to metabolism by a non-ACE kininase. 4. Identification and characterization of the putative non-ACE kininase which is inhibited by ACE inhibitors may reveal novel approaches to the tissue-specific modulation of kinin levels.     

Cultured fibroblasts in avian scleroderma, an autoimmune fibrotic disease, display an activated phenotype.

University of California, Davis, line 200 and 206 chickens spontaneously develop an autoimmune syndrome that has many features analogous to human scleroderma, including dermal fibrosis, antinuclear antibodies and antibodies to type II collagen. These birds also have thymic subcapsular epithelial defects and an abnormality in T cell calcium influx and proliferation in response to both T cell receptor-dependent and -independent activators. To determine whether fibroblast activation is a contributing factor to development of skin fibrosis in line 200/206 chickens, as it is in human scleroderma, we studied the collagen, non-collagenous protein and glycosaminoglycan (GAG) production of 34 separate fibroblast lines derived from the normal and fibrotic skin of line 200 and 206 chickens and from the skin of control chicken lines 058 and 254. The mean +/- SEM 24-h incorporation of 3H-proline or 3H-glucosamine into extracellular collagen, non-collagenous protein or GAG by first passage fibroblast lines derived from the fibrotic skin of diseased birds was 1,526 +/- 136, 859 +/- 82 and 25.7 +/- 1.3 dpm/10(3) cells, respectively, while fibroblast lines derived from the skin of control birds produced only 341 +/- 36, 343 +/- 42 and 15.2 +/- 1.4 dpm/10(3) cells. Similar differences in results were recorded for cell-associated production, and when collagen and non-collagenous protein production were assessed using non-radioactive electrophoretic methods. The activated phenotype of the fibroblast lines derived from the fibrotic skin of diseased birds persisted through 10 cell doublings in tissue culture. However, the ratio of type I:III collagen and the profile of GAG types produced were similar in all fibroblast lines studied. These results suggest that fibroblast activation is responsible for the skin fibrosis observed in this avian model of scleroderma.     

多巴酚丁胺负荷对缺血性扩张型心肌病患者左心室充盈的影响：病理生理学及预后意义

目的：本研究旨在探讨多巴酚丁胺对缺血性心肌病（ICM）患者左心室（LV）充盈功能的影响，并确定峰值负荷时限制性充盈型（RFP）是否具有预后预测价值。背景：ICM患者峰值负荷时RFP的预后价值尚属未知。方法：在静息和负荷情况下，采用多普勒超声心动检查研究了69例ICM患者；RFP定义为跨二尖瓣E／A比≥1．0、等容舒张时间（IVRT）〈80ms及E波减速时间（EDT）〈120ms。结果：69例患者中有42例静息时出现RFP，其中有24例患者负荷情况下转变为非RFP（EA），18例患者RFP持续存在（EE）；69例患者中27例静息和峰值负荷时均无RFP（AA）。     

Issues in selecting outcome measures to assess functional recovery after stroke

Most patients who survive a stroke experience some degree of physical recovery. Selecting the appropriate outcome measure to assess physical recovery is a difficult task, given the heterogeneity of stroke etiology, symptoms, severity, and even recovery itself. Despite these complexities, a number of strategies can facilitate the selection of functional outcome measures in stroke clinical trial research and practice. Clinical relevance in stroke outcome measures can be optimized by incorporating a framework of health and disability, such as the International Classification of Functioning, Disability, and Health (ICF). The ICF provides the conceptual basis for measurement and policy formulations for disability and health assessment. All outcome measures selected should also have sound psychometric properties. The essential psychometric properties are reliability, validity, responsiveness, sensibility, and established minimal clinically important difference. It is also important to establish the purpose of the measurement (discriminative, predictive, or evaluative) and to determine whether the purpose of the study is to evaluate the efficacy or effectiveness of an intervention. In addition, when selecting outcome measures and time of assessment, the natural history of stroke and stroke severity must be regarded. Finally, methods for acquiring data must also be considered. We present a comprehensive overview of the issues in selecting stroke outcome measures and characterize existing measures relative to these issues.     

Treatment strategies in advanced and metastatic cancer: differences in attitude between the USA, Canada and Europe.

Six-hundred and forty four radiation therapists from 21 European countries, Canada, and the USA responded to a questionnaire regarding the management of three cases of advanced cancer. The cases were a 64-year-old man with brain metastases from small cell carcinoma of the lung; a 64-year-old woman with bone metastases from carcinoma of the breast and a 59-year-old man with squamous cell carcinoma of the bronchus and mediastinal nodes. There was variation as to the perceived prognosis and appropriate aims of therapy, particularly for the case of squamous cell carcinoma of the bronchus. The total dose and number of fractions could be related to the perceived aims and expectations of treatment, for example, those aiming to extend life gave higher doses of radiotherapy and those aiming only to relieve symptoms gave lower. Similarly, those describing treatment as radical and estimating longer survival gave higher doses and more fractions than those treating palliatively. Variations in the role of the radiation oncologist in the management of advanced and metastatic cancer in the USA, Canada and Europe are discussed.     

Quality of life and voice following endoscopic resection or radiotherapy for early glottic cancer

Objectives: To assess whether proposed voice and quality of life (QoL) outcome measures were likely to be acceptable to patients previously treated for early glottic cancer by either radiotherapy or endoscopic resection, as well as looking for differences in QoL and voice between treatments. Design: Questionnaire‐based cohort study. Setting: Secondary care, three centres. Participants: All patients treated for T1a or in situ glottic carcinoma between 1997 and 2003. Fifty‐three patients were identified; those who had undergone salvage surgery or radiotherapy were excluded. A proportion refused to participate or could not be contacted and two patients had died of unrelated causes. Thirty‐six patients completed the trial with 18 from each treatment arm. Main outcome measures: Quality of voice as assessed by three questionnaires, Voice Handicap Index (VHI), Vocal Performance Questionnaire (VPQ), Voice Symptom Score (VoiSS) and perceptual analysis of voice by Grade, Roughness, Breathiness, Asthenia and Strained (GRBAS) assessment of vocal recordings. Quality of life as assessed by the Hospital Anxiety and Depression Scale (HADS), University of Washington Quality of Life Questionnaire (UW‐QoL), and the Functional Assessment of Cancer Therapy (FACT) questionnaire. Results: All patients included in the trial were able to complete the questionnaires; however, 19% required assistance of some kind. GRBAS assessment showed no difference between groups for any criteria. All QoL questionnaires gave equivalent good scores. All of the voice questionnaires showed no statistical difference between groups except for the emotional subscale of the VoiSS which showed a significantly better score for the radiotherapy arm (P = 0.04). Conclusion: All outcome measures were applicable and acceptable to the patient group. Overall QoL and voice appears similar despite treatment arm, apart from the emotional subscale of the VoiSS. A randomized controlled trial is required to further assess this question.     

q-Space diffusion of myelin-deficient spinal cords.

The apparent water diffusion anisotropy in white matter (WM) of excised spinal cords of myelin-deficient (md) rats and their age-matched controls was studied by high-b-value q-space diffusion MRS and MRI at different diffusion times. Non-monoexponential signal decay was observed at long diffusion times. The mean displacements in the md spinal cords were found to be higher than those of the controls. The apparent anisotropy (AA) of the fast-diffusing component was found to decrease more dramatically with the increase in diffusion time for the md spinal cords as compared with controls, whereas the AA of the slow-diffusing component in the controls was found to increase with the increase in diffusion time while that of the md cords decreased with the increase in diffusion time. When diffusion MRI was performed, similar diffusion anisotropy was extracted for the md and control spinal cords at diffusion times of 22 and 50 ms. Only at a diffusion time of about 200 ms was a significant difference obtained in the AA of the two groups. This originates from the much smaller increase in the mean displacement perpendicular to the fiber direction in the control group vs. the md group when the diffusion time was increased.