Dopamine receptor properties in Parkinson''s disease and Huntington''s chorea evaluated by positron emission tomography using 11C-N-methyl-spiperone

Dopaminergic receptor properties in the striatum of patients with Parkinson's disease (PD) and Huntington's chorea (HD) were studied by positron emission tomography (PET), using 11C-N-methyl-spiperone as a dopamine D2 receptor ligand. The time-dependent regional radioactive uptake in the caudate nucleus and the putamen was measured and fitted to a 3-compartment pharmacokinetic model. The rate constant k3 for specific binding to the receptor compartment in the striatum was determined in relation to the binding in regions with a low density of specific binding sites, such as the cerebellum and the frontal cortex . k3, which is a measure of the receptor density, was reduced in one patient with HD but less affected in PD in comparison with healthy controls. The pattern of k3 values calculated from the 6 PD patients is discussed in relation to any side-to-side differences in dopamine receptor densities in hemiparkinsonism and to possible "hypersensitivity" of dopamine receptors in the early stage of the disease and down-regulation in more advanced disease.     

Takayasu''s aortitis with renovascular hypertension

We report a case of Takayasu's disease with severe renovascular hypertension in a girl from Eritrea. In the "burn-out" phase after the erythrocyte sedimentation rate had normalized, reconstructive vascular surgery was performed as further progression of the disease seemed unlikely. However, probably due to her growth, the graft rotated and a second operation was successfully performed.     

Identification of a novel HLA-B*40 allele, HLA-B*4071, by sequence-based typing

HLA-B*4071 allele shows six nucleotides difference from B*4005 allele in exon 3 at nucleotides 419A>T, 420C>A, 463C>A, 477C>G, 486G>C and 527A>T, resulting in three amino acid changes Tyr116Leu, Arg131Ser and Glu152Val.     

Prediction of suboptimal primary cytoreduction in primary ovarian cancer with combined positron emission tomography/computed tomography--a prospective study

ObjectiveThe treatment of FIGO stage IB2 cervical cancer is controversial. Our aim was to assess treatment patterns, outcomes, and complications in patients with stage IB2 cervical cancer.MethodsA retrospective study of patients with stage IB2 cervical carcinoma at a single institution between January 1982 and September 2006 was performed. To adequately control treatment variables, we only included patients who underwent their entire treatment at our institution. Toxicity was assessed using NCI Common Toxicity Criteria (CTC).ResultsWe identified 82 patients, of whom 47 met the strict inclusion criteria. Of these, 27 patients (57%) underwent primary radical hysterectomy (RH) and 20 (43%) were treated with definitive radiation/chemoradiation therapy (RT/CRT). Patients selected for RT/CRT had a higher American Society of Anesthesiologist (ASA) score than those selected for surgery (P = 0.037). The 3-year progression free survival rate was 52% for the RH group and 55% for the RT/CRT group (P = 0.977). The 3-year overall survival rates were 72% and 55%, respectively (P = 0.161). Overall, 52% of patients in the RH group received postoperative radiation therapy as part of their adjuvant treatment. CTC grade 3, 4, and 5 complications affected 5 patients (19%) in the RH group and 3 (15%) in the RT/CRT group.ConclusionBoth RH and definitive RT/CRT are adequate management strategies for patients with FIGO stage IB2 cervical cancer. However, there was a subset of patients in whom RH as monotherapy was appropriate. Further studies are needed to evaluate the role of new preoperative models that will accurately identify these patients.     

Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus

Defective control of T cell apoptosis is considered to be one of the pathogenetic mechanisms in systemic lupus erythematosus (SLE). Oestrogen has been known to predispose women to SLE and also to exacerbate activity of SLE; however, the role of oestrogen in the apoptosis of SLE T cells has not yet been documented. In this study, we investigated the direct effect of oestrogen on the activation‐induced cell death of T cells in SLE patients. The results demonstrated that oestradiol decreased the apoptosis of SLE T cells stimulated with phorbol 12‐myristate 13‐acetate (PMA) plus ionomycin in a dose‐dependent manner. In addition, oestradiol down‐regulated the expression of Fas ligand (FasL) in activated SLE T cells at the both protein and mRNA levels. In contrast, testosterone increased FasL expression dose‐dependently in SLE T cells stimulated with PMA plus ionomycin. The inhibitory effect of oestradiol on FasL expression was mediated through binding to its receptor, as co‐treatment of tamoxifen, an oestrogen receptor inhibitor, completely nullified the oestradiol‐induced decrease in FasL mRNA expression. Moreover, pre‐treatment of FasL‐transfected L5178Y cells with either oestradiol or anti‐FasL antibody inhibited significantly the apoptosis of Fas‐sensitive Hela cells when two types of cells were co‐cultured. These data suggest that oestrogen inhibits activation‐induced apoptosis of SLE T cells by down‐regulating the expression of FasL. Oestrogen inhibition of T cell apoptosis may allow for the persistence of autoreactive T cells, thereby exhibiting the detrimental action of oestrogen on SLE activity.     

Which common clinical conditions should medical students be able to manage by graduation? A perspective from Australian interns

The objectives of the study were to report the development of a core curriculum that details the clinical conditions medical students should be able to manage upon graduation; and to canvass the opinion of interns (first-year postgraduate doctors) regarding their perceptions of the level of skill required to manage each condition. Literature relating to core curriculum development and training of junior medical officers was reviewed and stakeholders in the education and training of medical students and junior doctors in the state of New South Wales, Australia (intern supervisors, academics, registrars, nurses and interns) were consulted. The final curriculum spanned 106 conditions, 77 'differentiated' and 29 'undifferentiated'. Four levels of skill at which conditions should potentially be managed were also identified: 'Theoretical knowledge only'; 'Recognize symptoms and signs without supervision'; Initiate preliminary investigations, management and/or treatment without supervision'; and 'Total investigation, management and/or treatment without supervision'. The list of conditions in the curriculum was converted to a survey format and a one-in-two random sample of interns (n = 193) practising in New South Wales who graduated from the state's three medical schools were surveyed regarding the level of skill required for managing each clinical condition at graduation. A total of 51.3% of interns responded to the survey. Interns felt they should be able to initiate preliminary investigation, management and/or treatment for most conditions in the curriculum, with more than half acknowledging this level of management for 53 of the differentiated and 28 of the undifferentiated conditions. It is concluded that developing core curricula in medical education can involve multiple stakeholders, including junior doctors as the consumers of educational experiences. The data gathered may be useful to medical schools revising their curricula.     

Urokinase receptor-associated protein (uPARAP) is expressed in connection with malignant as well as benign lesions of the human breast and occurs in specific populations of stromal cells

The urokinase-type plasminogen activator (uPA) and the uPA receptor (uPAR) are key components in the plasminogen activation system, serving to promote specific events of extracellular matrix degradation in connection with tissue remodeling and cancer invasion. We recently described a new uPAR-associated protein (uPARAP), an internalization receptor that interacts with the pro-uPA:uPAR complex. In our study, we generated a specific polyclonal peptide antibody against human uPARAP and used it for the localization of uPARAP in different breast lesions. The affinity-purified antibodies specifically recognized uPARAP in Western blotting and gave a strong signal in immunohistochemistry. The immunohistochemic localization pattern was found to be identical to that of uPARAP mRNA as determined in parallel by in situ hybridization. uPARAP expression was then studied in both benign and malignant breast lesions. Whereas the normal breast tissue was uPARAP-negative, all benign lesions and ductal carcinoma in situ lesions showed immunoreactivity in fibroblast-like cells and myoepithelial cells associated with the lesion. In invasive carcinoma, uPARAP immunoreactivity was limited to tumor-associated mesenchymal cells. Double immunofluorescence analysis of invasive ductal carcinoma using antibodies against specific cell markers showed that uPARAP was localized in myofibroblasts and macrophages. No malignant cells, no endothelial cells and no vascular smooth muscle cells showed uPARAP immunoreactivity. We conclude that expression of uPARAP is associated with the abnormal breast and that expression appears in myofibroblasts, macrophages and myoepithelium. We suggest that uPARAP is involved in the clearance of the uPA:uPAR complex as well as other possible ligands during benign and malignant tissue remodeling.     

Efficacy of low-dose topotecan in second-line treatment for patients with epithelial ovarian carcinoma

BACKGROUND: The high incidence of dose-limiting myelosuppresion using the U.S. Food and Drug Administration-approved topotecan dose of 1.5 mg/m(2) for 5 days every 3 weeks may have limited its utility in the treatment of patients with epithelial ovarian carcinoma. The objective of the study was to evaluate the treatment results and toxicity of a low-dose topotecan regimen as second-line treatment for patients with epithelial ovarian carcinoma. METHODS: A retrospective analysis was conducted of 203 consecutive patients with primary epithelial ovarian carcinoma who were referred to the Finsen Center during the period from June, 1996 to June, 2000. Eligibility criteria included histopathologically documented, International Federation of Gynecology and Obstetrics (FIGO) Stage IC-IV epithelial ovarian carcinoma; first-line treatment with paclitaxel and a platinum compound; and second-line treatment with topotecan (1.0 mg/m(2) intravenously for 5 days every 3 weeks). Efficacy and toxicity were compared with published results from pivotal trials using the approved dose of topotecan of 1.5 mg/m(2) for the same indication. RESULTS: A total of 56 patients received second-line treatment with the reduced-dose topotecan regimen because of refractory, persistent, or recurrent disease. In the subgroup of patients with platinum-resistant and paclitaxel-resistant disease (n = 43 patients), the response rate of 11.6% (95% confidence interval [95%CI], 3.9-25.1%) was similar to the response rate of 12.4% (95%CI, 6.9-19.9%) in a pivotal trial using standard-dose topotecan. In patients with platinum-resistant and paclitaxel-resistant disease, the median progression free survival and overall survival from the first day of second-line topotecan treatment were 2.7 months (range, 0.7-19.5 months) and 6.0 months (range, 1.0-32.8 months), respectively. In a multivariate Cox analysis, the initial performance status (0 vs. 1-2; P = 0.040; hazard ratio [HR], 2.05) and the performance status at the time of second-line treatment (0 vs. 1-2; P < 0.001; HR, 4.50) were identified as independent prognostic factors for overall survival from the start of second-line treatment. Grade 4 neutropenia was noted in only 5.1% of reduced-dose topotecan cycles (95%CI, 2.8-8.4%) compared with 33% and 57% of standard-dose cycles in pivotal studies. CONCLUSIONS: Topotecan at a dose of 1.0 mg/m(2) has similar efficacy based on response rate and lower toxicity compared with the approved schedule of 1.5 mg/m(2) for 5 days every 3 weeks in second-line treatment for patients with platinum-resistant and paclitaxel-resistant epithelial ovarian carcinoma. However, a comparison of different topotecan doses and schedules preferably should be made in a randomized setting in well-characterized populations with regard to established prognostic factors.