Consensus statement on the bio-safety of urinary-derived gonadotrophins with respect to Creutzfeldt-Jakob disease

Human transmissible spongiform encephalopathies (TSE) encompass a group of rare neurodegenerative diseases. In April 2004, a group of international experts and regulators met in Buenos Aires, Argentina, to review the safety and to reach consensus on the use of urinary-derived gonadotrophins with respect to TSE. Iatrogenic transmission of Creutzfeldt-Jakob Disease (CJD) from pituitary-derived gonadotrophins has been reported, no infectivity in urine has been demonstrated, and no definite cases of transmission via urine have been reported. It is currently not possible to monitor donor urine or finished product for the presence of prions. Therefore the assessment of risk has to be based on the likelihood of infection in urine, the source of the urine, and the capacity of the manufacturing process to remove any adventitious infection. Urine for the production of medicinal products should be obtained from sources that minimize the possible presence of materials derived from subjects suffering from human TSE. As no strong evidence for TSE infectivity in urine exists, it can be concluded that the risk of disease-generating prions and TSE infectivity being present in donor urine is low. Current evidence indicates that, with respect to the risk of TSE infection, urinary-derived gonadotrophins appear to be safe.     

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

Prognostic significance of urokinase plasminogen activator receptor and its cleaved forms in blood from patients with non‐small cell lung cancer

Urokinase plasminogen activator (uPA) cleaves its three‐domain cell surface receptor, uPAR, liberating domain I [uPAR(I)] and leaving the cleaved uPAR(II‐III) on the cell surface. Both intact and cleaved uPAR can be shed from the cell surface. uPAR(I) was previously shown to be a prognostic factor in lung tumour extracts. Here we analyse uPAR forms in blood from patients with non‐small cell lung cancer (NSCLC). Preoperatively sampled plasma/serum from 32 patients with NSCLC was analysed. Three time‐resolved fluoroimmunoassays (TR‐FIAs) measuring intact uPAR(I‐III) (TR‐FIA 1), uPAR(I‐III) + uPAR(II‐III) (TR‐FIA 2) and uPAR(I) (TR‐FIA 3) were applied. The Spearman rank correlations between plasma and serum levels of uPAR(I‐III), uPAR(I‐III) + uPAR(II‐III), and uPAR(I) were 0.89, 0.94 and 0.68 respectively. Survival analysis demonstrated that high levels of all uPAR forms were associated with shorter survival. Adjusted for histological subtype high plasma uPAR(I‐III) and uPAR(I) levels as well as serum uPAR(I) levels were significantly associated with shorter OS (hazards ratios = 4.3, 2.8 and 3.8 respectively). High blood levels of intact uPAR and its cleaved forms are associated with poor prognosis in NSCLC.     

A clinical and epidemiologic study morsicatio buccarum/labiorum

abstract – A study of habitual self mutilation of the buccal and/or labial mucosa by biting was conducted on 8,589 persons attending the Royal Dental College, Copenhagen. Forty-two cases were found. The youngest patient was 5 years old and the oldest was 47. The condition occurred most frequently (1.77%) among persons aged 15–19 years. There was no difference in prevalence between males and females. Combined mutilation of cheek(s) and lip(s) was more frequent (62%) than isolated mutilation of the cheek(s) (24%) or isolated mutilation of the lip(s) (14%). Bilateral biting of the cheeks was more frequent than unilateral biting, and biting of the lower lip was more frequent than biting of the upper lip. Ninety-three per cent of the patients were aware of their habit, and most of them stated that they had been biting for years. Twenty patients were re-examined; in all but one patients the biting persisted but in 7 patients the location of the lesions had changed. In several cases a link could be traced to personal problems and mental stress. It was further noticed that many patients were students and white-collar workers, suggesting that "intellectual" work may predispose for the habit.     

Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers

AIMS: NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. METHODS: A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. RESULTS: Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 microg x ml(-1) h) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 h period. CONCLUSIONS: NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.     

PSYCHOLOGICAL EFFECTS OF AN EPIDEMIOLOGICAL STUDY OF BENIGN PROSTATIC HYPERTROPHY

SUMMARY The psychological impact of an epidemiological study of benign prostatic hypertrophy (BPH) was assessed in a representative sample of practice list patients. Of the 889 men completing a general health self-report questionnaire previously validated in a screening programme, 75% knew nothing of problems of the prostate, and 84.5% were not at all worried about prostate problems prior to commencement of the study. Receiving the letter of invitation and the procedures neither increased nor reduced anxiety levels for 69% and 70% respectively. In the 227 men referred to hospital for further investigation the procedure increased anxiety in 28%, decreased anxiety in 20%, and had no effect on the remainder. The sample of 137 (16%) men who, prior to interview, were in some way worried about problems of the prostate had significantly more urinary tract symptoms than those who were not at all worried about prostatic problems. Despite being worried about prostatic problems and having significant urinary symptoms, this group was no more likely to have attended a GP for investigation and/or treatment. Results are discussed in relation to the possible psychological effects of general health screening and the reluctance of men to attend for consultation despite awareness and concern regarding urinary symptomatology.