7alpha-Iodo and 7alpha-fluoro steroids as androgen receptor-mediated imaging agents.

We have synthesized several 7alpha-fluoro (F) and 7alpha-iodo (I) analogues of 5alpha-dihydrotestosterone (5alpha-DHT) and 19-nor-5alpha-dihydrotestosterone (5alpha-NDHT) and tested them for binding to the androgen receptor and for their biological activity in an in vitro assay with cells that have been engineered to respond to androgens. The relative binding affinity to the androgen receptor determined in competition assays showed that in the androstane series the fluoro steroids have the highest affinity and that F-17alpha-CH3-DHT (4) has a higher affinity than 5alpha-DHT. All other steroids were somewhat less potent than 5alpha-DHT with F-DHT (2) = I-17alpha-CH3-DHT (3) >/= F-NDHT (6) > F-17alpha-CH3-NDHT (8) = I-DHT (1) >/= I-NDHT (5) > I-17alpha-CH3-NDHT (7). The relative biological activity in cells transfected with the androgen receptor and an androgen responsive reporter gene is 4 > 5alpha-DHT > 2 > 6 > 3 >/= 1 >/= 8 >/= 5 > 7. The iodinated compound, I-17alpha-CH3-DHT (3), with the highest binding activity was synthesized labeled with 125I and was shown to bind with high affinity, Ka = 1.9 x 10(10) L/mol, and low nonspecific binding to the androgen receptor in rat prostatic cytosol. However, when radiolabeled [125I]-17alpha-CH3-DHT ([125I]3) was injected into castrated male rats, it showed very poor androgen receptor-mediated uptake into the rat prostate. This was unexpected in light of its superior receptor binding properties and its protection by the 17alpha-methyl group from metabolic oxidation at C-17. However, the biological potency of I-17alpha-CH3-DHT (3) was not as high as would have been expected. When I-DHT (1) and I-17alpha-CH3-DHT (3) were incubated in aqueous media at 37 degrees C they rapidly decomposed, but they were stable at 0 degrees C. The fluorinated analogue 4 treated similarly at 37 degrees C was completely stable. The products of the decomposition reaction of I-DHT (1) at 37 degrees C were identified as iodide and principally 17beta-hydroxy-5alpha-androst-7-en-3-one. The temperature dependence of this elimination reaction explains the inconsistency between the high binding to the androgen receptor (measured at 0 degrees C) and the low biological activity, as well as the poor androgen receptor mediated concentration in vivo. The fluorinated analogue F-17alpha-CH3-DHT (4) has both high affinity for the androgen receptor and high stability in aqueous media. Of the compounds tested, 4 has the highest affinity for the androgen receptor as well as the highest androgenic activity. Thus it is likely that F-17alpha-CH3-DHT 4 labeled with 18F will be an excellent receptor-mediated diagnostic imaging agent.     

Sensitivity and specificity of brain stem potentials as a means of differentiating cochlear and retrocochlear disorders (acoustic neuromas)

Between 1980 and 1985 we examined a fairly large group of patients for retrocochlear disorders. Every patient was examined by at least two procedures, registration of brain stem potentials and CT; we had also magnetic resonance images taken of some of these patients. We diagnosed a total of 37 acoustic neuromas in 34 of the patients examined. From our study a conclusion can be drawn about the sensitivity and specificity of brain stem potentials as evidence of an acoustic neuroma. The rate of false negative diagnoses is about 6%. The false positive rate is considerably higher, and it is discussed in detail. The clinical utility of brain stem potentials is illustrated with two case histories. Because of the method's low false negative rate, cochlear disorders diagnosed by registering brain stem potentials need not as a rule be confirmed by modern imaging procedures.     

Clearanceverhalten der Niere gegenüber ANF im autologen hundetransplantationsmodell

Zusammenfassung ANF ist ein zyklisches Peptid, das mit einem MG von 20 000 vollständig von der Niere filtriert und in den Bürstensäumen der Tubuli abgebaut wird. In einem tierexperimentellen Modell wurde untersucht, inwieweit dieses Ausscheidungsverhalten nach 48 h Ischämiebelastung bei HTK-Protektion verändert ist. Gleichzeitig wurde der ANF/Renin-Antagonismus untersucht. In den Ergebnissen zeigte sich, daß auch nach 48 h Ischämiebelastung die für den Abbau von ANF verantwortlichen Endopeptidasen intakt und durch die Ischämie nicht beeinträchtigt sind. Es besteht eine lineare Beziehung zwischen den Konzentrationen von ANF im nierenvenösen und systemisch-arteriellen Blut. In den Versuchen kann nicht gezeigt werden, daß ein Antagonismus zwischen dem ANF- und Renin-System besteht. Möglicherweise kann ANF als weiterer Ischämieparameter gewertet werden.

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Clearance of ANF in the canine kidney in an autologous transplant model

Summary ANF is totally fltrated by the kidney and is degradated in the brush border of the tubuli. In an experimental transplant model in dogs excretion of ANF is investigated after a cold ischemia period of 48 h and HTK-protection. The ANF-renin-antagonism was of interest respectively. The experiments demonstrated that the filtration in the glomeruli and the function of the endopeptidases in the brush border is normal after a cold ischemia period of 48 and HTK-protection. There is a linear correlation between the concentration of ANF in the renal vein and the aorta. An antagonism of ANF and renin could not be found. ANF is discussed as an additional ischemia parameter in renal transplantation.

Mit Unterstützung der Deutschen Forschungsgemeinschaft —SFB 330 Organprotektion Göttingen     

Aged venous thrombi: radioimmunoimaging with fibrin-specific monoclonal antibody

Radioimmunoimaging of fresh canine venous thrombi with a murine monoclonal antibody specific for human and dog fibrin has been reported. Successful imaging of canine deep venous thrombi 1, 3, and 5 days old at the time of antibody injection is reported. Images were positive in all dogs, and the uptake of fibrin-specific antibody was equivalent to that of fresh thrombi.     

Vancomycin-resistant Staphylococcus aureus isolate from a patient in Pennsylvania

A vancomycin-resistant Staphylococcus aureus (VRSA) isolate was obtained from a patient in Pennsylvania in September 2002. Species identification was confirmed by standard biochemical tests and analysis of 16S ribosomal DNA, gyrA, and gyrB sequences; all of the results were consistent with the S. aureus identification. The MICs of a variety of antimicrobial agents were determined by broth microdilution and macrodilution methods following National Committee for Clinical Laboratory Standards (NCCLS) guidelines. The isolate was resistant to vancomycin (MIC = 32 micro g/ml), aminoglycosides, beta-lactams, fluoroquinolones, macrolides, and tetracycline, but it was susceptible to linezolid, minocycline, quinupristin-dalfopristin, rifampin, teicoplanin, and trimethoprim-sulfamethoxazole. The isolate, which was originally detected by using disk diffusion and a vancomycin agar screen plate, was vancomycin susceptible by automated susceptibility testing methods. Pulsed-field gel electrophoresis (PFGE) of SmaI-digested genomic DNA indicated that the isolate belonged to the USA100 lineage (also known as the New York/Japan clone), the most common staphylococcal PFGE type found in hospitals in the United States. The VRSA isolate contained two plasmids of 120 and 4 kb and was positive for mecA and vanA by PCR amplification. The vanA sequence was identical to the vanA sequence present in Tn1546. A DNA probe for vanA hybridized to the 120-kb plasmid. This is the second VRSA isolate reported in the United States.     

福建省高校贫困大学生心理健康水平与人格特征

目的:了解贫困生的心理健康现状和人格特征。方法:于2005-09/11随机抽取福州大学、福建师范大学、福建农林大学、福建中医学院、闽江学院2002-2004级学生2400名。男1478名,女922名,平均(20±1)岁。根据2004-11-04福建省福州市政府办公厅正式下发的《福州市人民政府关于提高城区城镇及农村居民最低生活保障标准的通知》中的规定,即城镇多人户每人每个月210元、单人户230元;农村多人户每人每月155元、单人户175元,本文把家庭人均月收入较少,有一定数额债务,只能缴纳部分学杂费,基本生活费接近于当地居民最低生活保障线(如上规定,本文以230元为基准)的学生定为“贫困生”。采用精神症状自评量表和16种人格因素问卷对高校贫困生的心理健康和人格特征进行调查。结果:发放问卷2400份,收回有效问卷2111份。其中贫困生539份。①贫困生精神症状自评量表的躯体化、强迫、人际敏感、抑郁、焦虑、敌对、恐怖、偏执、精神病性、其他、总症状指数得分均高于非贫困生(贫困生:1.61±0.56,2.02±0.64,1.92±0.63,1.71±0.56,1.65±0.58,1.73±0.68,1.57±0.62,1.81±0.65,1.67±0.54,1.76±0.63,1.74±0.49;非贫困生:1.48±0.45,1.89±0.56,1.79±0.57,1.61±0.51,1.54±0.50,1.61±0.56,1.44±0.49,1.66±0.54,1.54±0.46,1.61±0.53,1.62±0.41,P<0.01)。男女贫困生之间各因子分差异均不显著(P>0.05)。②福建省高校贫困大学生的心理问题检出率为24.5%,其中轻度心理问题(2≤因子分<3)为22.6%;中度心理问题(3≤因子分<4)为1.7%;重度心理问题(4≤因子分<5)为0.2%。心理问题以强迫、人际敏感、偏执、忧郁、敌对、焦虑等心理问题最为突出。③16种人格因素问卷中,贫困生乐群性、聪慧性、兴奋性、敏感性、怀疑性上得分低于非贫困生,有恒性、忧虑性、独立性得分高于非贫困生(贫困生:5.20±1.77,4.70±1.93,5.49±1.87,6.46±1.79,4.29±1.71,4.60±1.63,6.64±1.82,5.07±1.82;非贫困生:5.39±1.74,4.95±1.99,5.82±1.91,6.66±1.75,4.55±1.77,4.36±1.69,6.43±1.94,4.89±1.77,P<0.05～0.01)。④影响贫困生心理健康水平的主要人格因素按其影响作用从大到小有怀疑性、忧虑性、稳定性、兴奋性、自律性。结论:福建省高校贫困大学生的心理健康状况令人担忧,其人格特征对心理健康水平有重要影响。