Detection and partial purification of a potent mitogenic factor for human thyroid follicular cells.

Normal adult human thyroid follicular cells have an extremely limited proliferative capacity in vitro. No previously studied mitogen, including thyrotropin (TSH) or epidermal growth factor (EGF), has in our hands resulted in a significant improvement over the 3-4% nuclear [3H]thymidine pulse-labelling index (LI) obtainable with 10% fetal calf serum. Here we report the detection in the conditioned medium from a sub-clone of NIH3T3 fibroblasts of a mitogenic activity capable of increasing this response up to 10-fold, to an LI of over 20%, together with an even greater relative stimulation of mitotic activity. Preliminary characterisation has excluded EGF and TGF alpha, and demonstrated that the activity is bound reversibly by heparin-Sepharose, thus pointing to a member of the heparin-binding fibroblast- or hepatocyte-growth factor families. This material should have wide practical application in facilitating primary culture of follicular cells, and may reveal new mechanisms of stromal-epithelial interaction regulating normal and neoplastic thyroid growth in vivo.     

Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.

GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.     

The potentiation of adrenaline-induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.

1. Aggregation in platelet-rich plasma from normotensive men was induced by adrenaline (0.25-16 microM), ADP (0.25-16 microM), collagen (0.25-8 micrograms ml-1) or serotonin (10 microM) alone, or by previously sub-threshold concentrations of adrenaline (0.03-1 microM) in combination with sub-threshold concentrations of serotonin (2.5 microM), ADP (0.5 microM) or collagen (0.125 micrograms ml-1). The effects of the alpha 1-adrenoceptor blockers naftopidil and doxazosin on platelet aggregation were investigated. 2. The dose-response curves for collagen and ADP were unaffected by either drug. However, naftopidil (40 microM) inhibited serotonin-induced platelet aggregation (23.9%, 95% confidence interval (CI) 10.7 to 37.1%; P < 0.01) and caused a slight shift to the right of the adrenaline dose-response curve with a mean increase in the EC50 value of 0.5 microM (95% CI 0.07 to 0.93 microM; P < 0.05). Doxazosin had no effect on serotonin or adrenaline-induced aggregation. 3. A marked potentiation of the aggregation induced by subthreshold concentrations of adrenaline resulted from the prior addition of low concentrations of ADP, collagen or serotonin. 4. These potentiated responses were inhibited in a dose-dependent manner by naftopidil and to a lesser extent doxazosin. The maximum inhibitions (%) produced by naftopidil (40 microM) on the responses of adrenaline potentiated by ADP were 58.3% (95% CI 36.8 to 79.8%; P < 0.001), serotonin 58.9% (95% CI 40.0 to 77.8%; P < 0.001), and collagen 70.9% (95% CI 52.5 to 89.3%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

LIMITATIONS OF RADIOTHERAPY IN THE DEFINITIVE TREATMENT OF SQUAMOUS CARCINOMA OF THE TONSILLAR FOSSA

Between 1970 and 1990, 104 patients with squamous cell carcinoma (SCC) of the tonsil were treated. The median age was 58 years and 80% of patients were males. Distribution among clinical stages was: stage I, 19 patients; stage II, 12 patients; stage III, 23 patients; and stage IV, 48 patients. More than 70% of patients had initial radiotherapy as definitive treatment irrespective of stage, reflecting the treatment philosophy over much of this period. The overall survival rate was 26% at 5 years, with survival being significantly affected by T stage, clinical stage and age. Clinical node status did not significantly affect survival rates. Good local control of T₁N₀ cancers was achieved with radiotherapy alone, but patients with more advanced cancers did poorly. We have now moved away from a non-selective policy and use initial surgery combined with postoperative radiotherapy in most patients, reserving radiotherapy alone for mainly early tonsil cancers.     

CT visualization of medullary sponge kidney

Recognizing the changes of medullary sponge kidney (MSK) on computed tomographic (CT) scans may be of value in both diagnosis and in differentiating this from other disease states. The appearance on CT of MSK has not previously been well described. A case is reported that demonstrates ectatic renal collecting tubules visualized by CT, and techniques are suggested to optimize visualization of these changes.     

Retinal vasculitis

Evidence is now accumulating on both clinical and experimental grounds that the retina is an a priori source of inflammatory activity. Reactive inflammation in the retina may produce many of the clinical signs previously ascribed to uveal inflammation. Autoimmune mechanisms are probably responsible for the majority of cases of retinal vasculitis. Autoimmune retinal vasculitis occurs without other classical signs of inflammatory response in any other parts of the body. When associated systemic manifestations occur they may reflect different underlying immunopathogenic abnormalities. Thus in diseases with predominantly arterial involvement (e.g. systemic lupus erythematosus, polyarteritis nodosa) the retinal arteries bear the brunt of this disease. In Behçet''s disease the systemic involvement is usually venous and ocular involvement produces diffuse capillary and venous inflammation with areas of retinal necrosis and major vascular occlusion. The retinal appearances differ from sarcoidosis in which a granulomatous response produces characteristic periphlebitis. Finally, autoimmune retinal vasculitis produces diffuse capillary and venous damage, without any systemic signs. In the next decade the search will be for the identification of the specific antigens initiating these disparate retinal features. Retinal S antigen is a potent antigen, but rhodopsin, interphotoreceptor binding protein, and transducin all need further experimental investigation. Precise documentation will herald the dawn of new therapeutic measures based on a sound immunological fabric.     

儿童焦虑症治疗的第一步

约有6%～20%的儿童和青少年患有广泛性焦虑、分离性焦虑和社交恐惧症,但是临床医生对于儿童和青少年的精神障碍认识尚不充分.这一问题非常严重,因为如果发病年龄小、病情较重,那么患者成人之后的结局往往很差.此外,如果不能早期诊断,焦虑症、抑郁症和药物滥用的发生率就会增加.在最近的<新英格兰医学杂志>中,发表了由Walkup等人进行的有关儿童-青少年焦虑症的多模型研究(CAMS)的结果,该项研究对上述精神障碍早期治疗的必要性进行了论述.